identify potential deficiencies: Topics by Science.gov

Sample records for identify potential deficiencies

Calcium-deficiency assessment and biomarker identification by an integrated urinary metabonomics analysis

PubMed Central

2013-01-01

Background Calcium deficiency is a global public-health problem. Although the initial stage of calcium deficiency can lead to metabolic alterations or potential pathological changes, calcium deficiency is difficult to diagnose accurately. Moreover, the details of the molecular mechanism of calcium deficiency remain somewhat elusive. To accurately assess and provide appropriate nutritional intervention, we carried out a global analysis of metabolic alterations in response to calcium deficiency. Methods The metabolic alterations associated with calcium deficiency were first investigated in a rat model, using urinary metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis. Correlations between dietary calcium intake and the biomarkers identified from the rat model were further analyzed to confirm the potential application of these biomarkers in humans. Results Urinary metabolic-profiling analysis could preliminarily distinguish between calcium-deficient and non-deficient rats after a 2-week low-calcium diet. We established an integrated metabonomics strategy for identifying reliable biomarkers of calcium deficiency using a time-course analysis of discriminating metabolites in a low-calcium diet experiment, repeating the low-calcium diet experiment and performing a calcium-supplement experiment. In total, 27 biomarkers were identified, including glycine, oxoglutaric acid, pyrophosphoric acid, sebacic acid, pseudouridine, indoxyl sulfate, taurine, and phenylacetylglycine. The integrated urinary metabonomics analysis, which combined biomarkers with regular trends of change (types A, B, and C), could accurately assess calcium-deficient rats at different stages and clarify the dynamic pathophysiological changes and molecular mechanism of calcium deficiency in detail. Significant correlations between calcium intake and two biomarkers, pseudouridine (Pearson correlation, r = 0.53, P = 0.0001) and citrate (Pearson correlation, r = -0.43, P = 0.001), were further confirmed in 70 women. Conclusions To our knowledge, this is the first report of reliable biomarkers of calcium deficiency, which were identified using an integrated strategy. The identified biomarkers give new insights into the pathophysiological changes and molecular mechanisms of calcium deficiency. The correlations between calcium intake and two of the biomarkers provide a rationale or potential for further assessment and elucidation of the metabolic responses of calcium deficiency in humans. PMID:23537001
Minimizing preventable trauma deaths in a limited-resource setting: a test-case of a multidisciplinary panel review approach at the Komfo Anokye Teaching Hospital in Ghana.

PubMed

Yeboah, Dominic; Mock, Charles; Karikari, Patrick; Agyei-Baffour, Peter; Donkor, Peter; Ebel, Beth

2014-07-01

Our objectives were to determine the proportion of preventable trauma deaths at a large trauma hospital in Kumasi, Ghana, and to identify opportunities for the improvement of trauma care. A multidisciplinary panel of experts evaluated pre-hospital, hospital, and postmortem data of consecutive trauma patients who died over a 5-month period in 2006-2007 at the Komfo Anokye Teaching Hospital. The panel judged the preventability of each death. For preventable and potentially preventable deaths, deficiencies in care that contributed to their deaths were identified. The panel reviewed 231 trauma deaths. Of these, 84 charts had sufficient information to review preventable factors. The panel determined that 23 % of trauma deaths were definitely preventable, 37 % were potentially preventable, and 40 % were not preventable. One main deficiency in care was identified for each of the 50 definitely preventable and potentially preventable deaths. The most common deficiencies were pre-hospital delays (44 % of the 50 deficiencies), delay in treatment (32 %), and inadequate fluid resuscitation (22 %). Among the 19 definitely preventable deaths, the most common cause of death was hemorrhage (47 %), and the most common deficiencies were inadequate fluid resuscitation (37 % of deficiencies in this group) and pre-hospital delay (37 %). A high proportion of trauma fatalities might have been preventable by decreasing pre-hospital delays, adequate resuscitation in hospital, and earlier initiation of care, including definitive surgical management. The study also showed that preventable death panel reviews are a feasible and useful quality improvement method in the study setting.
Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD).

PubMed

McCullagh, Brian N; Comellas, Alejandro P; Ballas, Zuhair K; Newell, John D; Zimmerman, M Bridget; Azar, Antoine E

2017-01-01

Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis.
Antibody deficiency in patients with frequent exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

PubMed Central

McCullagh, Brian N.; Comellas, Alejandro P.; Ballas, Zuhair K.; Newell, John D.; Zimmerman, M. Bridget

2017-01-01

Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis. PMID:28212436
Physicians' assessment of pediatric returns to the Emergency Department.

PubMed

Easter, Joshua S; Bachur, Richard

2013-03-01

Return visits to the Emergency Department (ED) requiring admission are frequently reviewed for the purpose of quality improvement. Treating physicians typically perform this review, but it is unclear if they accurately identify the reasons for the returns. To assess the characteristics of pediatric return visits to the ED, and the ability of treating physicians to identify the root causes for these return visits. This retrospective cohort study reviewed all returns within 96 h of an initial visit over a 2-year period at a tertiary care pediatric ED. Baseline characteristics were determined from review of patients' charts. The treating physicians, the primary author, and independent reviewers identified the root cause for the returns. There were 97,374 patients that presented to the ED during the study, and 1091 (1.1%) of these children returned to the ED and were admitted. Returns were most common among children aged<5 years, arriving between 3:00 p.m. and 11:00 p .m. via private transportation, with infectious diseases. The physician involved in the care of the patient attributed 3.1% of returns to potential deficiencies in medical management, whereas the independent reviewers attributed 13% to potential deficiencies. Both returns and the subset of returns due to potential deficiencies in management are more common than previously estimated, rendering review of returns a valuable quality improvement tool. However, EDs should not rely exclusively on the treating physicians to identify the reason for returns, as they seem to underestimate the frequency of returns due to potential deficiencies in medical management. Copyright © 2013 Elsevier Inc. All rights reserved.
Projected future distribution of date palm and its potential use in alleviating micronutrient deficiency.

PubMed

Shabani, Farzin; Kumar, Lalit; Nojoumian, Amir Hadi; Esmaeili, Atefeh; Toghyani, Mehdi

2016-03-15

Micronutrient deficiency develops when nutrient intake does not match nutritional requirements for maintaining healthy tissue and organ functions which may have long-ranging effects on health, learning ability and productivity. Inadequacy of iron, zinc and vitamin A are the most important micronutrient deficiencies. Consumption of a 100 g portion of date flesh from date palm (Phoenix dactylifera L.) has been reported to meet approximately half the daily dietary recommended intake of these micronutrients. This study investigated the potential distribution of P. dactylifera under future climates to address its potential long-term use as a food commodity to tackle micronutrient deficiencies in some developing countries. Modelling outputs indicated large shifts in areas conducive to date palm cultivation, based on global-scale alteration over the next 60 years. Most of the regions suffering from micronutrient deficiencies were projected to become highly conducive for date palm cultivation. These results could inform strategic planning by government and agricultural organizations by identifying areas to cultivate this nutritionally important crop in the future to support the alleviation of micronutrient deficiencies. © 2015 Society of Chemical Industry.
The underestimated problem of using serum magnesium measurements to exclude magnesium deficiency in adults; a health warning is needed for "normal" results.

PubMed

Ismail, Yasmin; Ismail, Abbas A; Ismail, Adel A A

2010-03-01

A major use of serum magnesium measurements in clinical practice is to identify patients with deficiency. However, numerous studies have shown that magnesium deficiency is common and may be present in over 10% of hospitalized patients, as well as in the general population. An important cause for under diagnosis of deficiency is that serum magnesium, the most commonly used test, can be normal despite negative body stores. This article focuses on the limitations of "normal" magnesium results and highlights the importance of lifestyle or "modus vivendi" as a pragmatic means of identifying those individuals potentially at risk for negative body magnesium stores. Researched peer reviewed articles on magnesium published between 1990 and 2008 in MEDLINE and EMBASE, using database keywords "magnesium, deficiency, diagnosis, treatment and hypomagnesaemia". Bibliographies of retrieved articles have been searched and followed. We have also performed a manual search of each individual issue in which most of these reports have appeared. In 183 peer reviewed studies published from 1990 to 2008, magnesium deficiency was associated with increased prevalence and risk in 11 major conditions. Similarly, in 68 studies performed over the same period, magnesium deficiency was found to predict adverse events and a decreased risk of pathology was noted when supplementation or treatment was instituted. The perception that "normal" serum magnesium excludes deficiency is common among clinicians. This perception is probably enforced by the common laboratory practice of highlighting only abnormal results. A health warning is therefore warranted regarding potential misuse of "normal" serum magnesium because restoration of magnesium stores in deficient patients is simple, tolerable, inexpensive and can be clinically beneficial.
Assessment of the availability of technology for trauma care in Nepal.

PubMed

Shah, Mihir Tejanshu; Bhattarai, Suraj; Lamichhane, Norman; Joshi, Arpita; LaBarre, Paul; Joshipura, Manjul; Mock, Charles

2015-09-01

We sought to assess the availability of technology-related equipment for trauma care in Nepal and to identify factors leading to optimal availability as well as deficiencies. We also sought to identify potential solutions addressing the deficits in terms of health systems management and product development. Thirty-two items for large hospitals and sixteen items for small hospitals related to the technological aspect of trauma care were selected from the World Health Organization's Guidelines for Essential Trauma Care for the current study. Fifty-six small and 29 large hospitals were assessed for availability of these items in the study area. Site visits included direct inspection and interviews with administrative, clinical, and bioengineering staff. Deficiencies of many specific items were noted, including many that were inexpensive and which could have been easily supplied. Shortage of electricity was identified as a major infrastructural deficiency present in all parts of the country. Deficiencies of pulse oximetry and ventilators were observed in most hospitals, attributed in most part to frequent breakdowns and long downtimes because of lack of vendor-based service contracts or in-house maintenance staff. Sub-optimal oxygen supply was identified as a major and frequent deficiency contributing to disruption of services. All equipment was imported except for a small percent of suction machines and haemoglobinometers. The study identified a range of items which were deficient and whose availability could be improved cost-effectively and sustainably by better planning and organisation. The electricity deficit has been dealt with successfully in a few hospitals via direct feeder lines and installation of solar panels; wider implementation of these methods would help solve a large portion of the technological deficiencies. From a health systems management view-point, strengthening procurement and stocking of low cost items especially in remote parts of the country is needed. From a product development view-point, there is a need for robust pulse-oximeters and ventilators that are lower cost and which have longer durability and less need for repairs. Increasing capabilities for local manufacture is another potential method to increase availability of a range of equipment and spare parts. Copyright © 2015 Elsevier Ltd. All rights reserved.
Drug-micronutrient interactions: food for thought and thought for action.

PubMed

Karadima, Vasiliki; Kraniotou, Christina; Bellos, George; Tsangaris, George Th

2016-01-01

Micronutrients are indispensable for a variety of vital functions. Micronutrient deficiencies are a global problem concerning two billion people. In most cases, deficiencies are treatable with supplementation of the elements in lack. Drug-nutrient interactions can also lead to micronutrient reduce or depletion by various pathways. Supplementation of the elements and long-term fortification programs for populations at risk can prevent and restore the related deficiencies. Within the context of Predictive, Preventive, and Personalized Medicine, a multi-professional network should be developed in order to identify, manage, and prevent drug-micronutrient interactions that can potentially result to micronutrient deficiencies.
A sulphur deficiency-induced gene, sdi1, involved in the utilization of stored sulphate pools under sulphur-limiting conditions has potential as a diagnostic indicator of sulphur nutritional status.

PubMed

Howarth, Jonathan R; Parmar, Saroj; Barraclough, Peter B; Hawkesford, Malcolm J

2009-02-01

A sulphate deficiency-induced gene, sdi1, has been identified by cDNA-amplified fragment length polymorphism (AFLP) analysis utilizing field-grown, nutrient-deficient wheat (Triticum aestivum var. Hereward). The expression of sdi1 was specifically induced in leaf and root tissues in response to sulphate deficiency, but was not induced by nitrogen, phosphorus, potassium or magnesium deficiency. Expression was also shown to increase in plant tissues as the external sulphate concentration in hydroponically grown plants was reduced from 1.0 to 0.0 mm. On this basis, sdi1 gene expression has potential as a sensitive indicator of sulphur nutritional status in wheat. Genome-walking techniques were used to clone the 2.7-kb region upstream of sdi1 from genomic DNA, revealing several cis-element motifs previously identified as being associated with sulphur responses in plants. The Arabidopsis thaliana gene most highly homologous to sdi1 is At5g48850, which was also demonstrated to be induced by sulphur deficiency, an observation confirmed by the analysis of microarray data available in the public domain. The expression of Atsdi1 was induced more rapidly than previously characterized sulphur-responsive genes in the period immediately following the transfer of plants to sulphur-deficient medium. Atsdi1 T-DNA 'knockout' mutants were shown to maintain higher tissue sulphate concentrations than wild-type plants under sulphur-limiting conditions, indicating a role in the utilization of stored sulphate under sulphur-deficient conditions. The structural features of the sdi1 gene and its application in the genetic determination of the sulphur nutritional status of wheat crops are discussed.
Use of natural variation reveals core genes in the transcriptome of iron-deficient Arabidopsis thaliana roots

PubMed Central

Stein, Ricardo J.; Waters, Brian M.

2012-01-01

Iron (Fe) is an essential mineral micronutrient for plants and animals. Plants respond to Fe deficiency by increasing root uptake capacity. Identification of gene networks for Fe uptake and homeostasis could result in improved crop growth and nutritional value. Previous studies have used microarrays to identify a large number of genes regulated by Fe deficiency in roots of three Arabidopsis ecotypes. However, a large proportion of these genes may be involved in secondary or genotype-influenced responses rather than in a universal role in Fe uptake or homeostasis. Here we show that a small percentage of the Fe deficiency transcriptome of two contrasting ecotypes, Kas-1 and Tsu-1, was shared with other ecotypes. Kas-1 and Tsu-1 had different timing and magnitude of ferric reductase activity upon Fe withdrawal, and different categories of overrepresented Fe-regulated genes. To gain insights into universal responses of Arabidopsis to Fe deficiency, the Kas-1 and Tsu-1 transcriptomes were compared with those of Col-0, Ler, and C24. In early Fe deficiency (24–48 h), no Fe-downregulated genes and only 10 upregulated genes were found in all ecotypes, and only 20 Fe-downregulated and 58 upregulated genes were found in at least three of the five ecotypes. Supernode gene networks were constructed to visualize conserved Fe homeostasis responses. Contrasting gene expression highlighted different responses to Fe deficiency between ecotypes. This study demonstrates the use of natural variation to identify central Fe-deficiency-regulated genes in plants, and identified genes with potential new roles in signalling during Fe deficiency. PMID:22039296
Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review.

PubMed

Tan, Hu; Chen, Xin; Lv, Weigang; Linpeng, Siyuan; Liang, Desheng; Wu, Lingqian

2018-04-27

3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency.
Vitamin D in Lupus

PubMed Central

Kamen, Diane L.

2014-01-01

Vitamin D is an essential steroid hormone, with well-established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease flare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases. PMID:20969555
Prevalence and Risk Factors for Iron Deficiency Anemia and Iron Depletion During Pregnancy: A Prospective Study.

PubMed

Gomes da Costa, Ana; Vargas, Sara; Clode, Nuno; M Graça, Luís

2016-09-01

Anemia and iron deficiency during pregnancy are a worldwide concern and are more frequent among women of reproductive age, pregnant women, and young children. The aim of this study was to assess the prevalence of iron deficiency anemia and the risk factors for iron depletion during the first half of pregnancy, in a Portuguese population. A prospective study was conducted at a tertiary hospital and included pregnant women, until the 20th week of gestation. Data was collected regarding demographic and pregnancy features and hemoglobin and serum ferritin concentrations were determined. A multivariate logistic regression was performed to identify potential risk factors for iron deficiency. Two hundred and one women were included, from which five (2.49%) presented anemia. Additionally, 77 (38.3%) exhibited iron deficiency and 22 (10.9%) revealed severe iron depletion. Maternal age was the only risk factor identified. The odds ratio (OR) was equal to 12.99 (95% CI 2.41 - 70.0) for women under twenty years of age and 2.09 (95% CI 1.05 - 4.14) for women older than thirty years of age. The prevalence of maternal anemia in the first half of pregnancy was lower than in other studies. However, more than one-third of the women exhibited iron deficiency. With the exception of maternal age, no other risk factors were identified.
Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

PubMed

Tang, Yew Chung; Ho, Szu-Chi; Tan, Elisabeth; Ng, Alvin Wei Tian; McPherson, John R; Goh, Germaine Yen Lin; Teh, Bin Tean; Bard, Frederic; Rozen, Steven G

2018-03-22

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers. To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data. The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets. Six genes showed PTEN-SSL patterns of activity in a large proportion of PTEN-deficient breast cancer cell lines and are potential specific vulnerabilities in PTEN-deficient breast cancer. Furthermore, the NUAK1 PTEN-SSL vulnerability identified by RNA interference techniques can be recapitulated and exploited using the small molecule kinase inhibitor HTH-01-015. Thus, NUAK1 inhibition may be an effective strategy for precision treatment of PTEN-deficient breast tumors.
[Maternal and neonatal vitamin B12 deficiency detected by expanded newborn screening].

PubMed

Papp, Ferenc; Rácz, Gábor; Lénárt, István; Kóbor, Jenő; Bereczki, Csaba; Karg, Eszter; Baráth, Ákos

2017-12-01

Infant vitamin B 12 deficiency can manifest as a severe neurodegenerative disorder and is usually caused by maternal deficiency due to vegetarian diet or pernicious anaemia. Its early recognition and treatment can prevent potentially serious and irreversible neurologic damage. Biochemically, vitamin B 12 deficiency leads to an accumulation of methylmalonic acid, homocysteine, and propionylcarnitine. Expanded newborn screening using tandem mass spectrometry may identify neonatal and maternal vitamin B 12 deficiency by measurement of propionylcarnitine and other metabolites in the dried blood spot sample of newborns. To summarize our experiences gained by screening for vitamin B 12 deficiency. Clinical and laboratory data of vitamin B 12 -deficient infants diagnosed in Szeged Screening Centre were retrospectively analysed. In Hungary, expanded newborn screening was introduced in 2007. Since then approximately 395 000 newborns were screened in our centre and among them, we identified four newborns with vitamin B 12 deficiency based on their screening results. In three cases an elevated propionylcarnitine level and in the fourth one a low methionine level were indicative of vitamin B 12 deficiency. We also detected an additional vitamin B 12 -deficient infant with neurological symptoms at 4 months of age, after a normal newborn screening, because of elevated urinary methylmalonic acid concentration. Vitamin B 12 deficiency was secondary to maternal autoimmune pernicious anaemia in all the five infants. As a result of the recognized cases the incidence of infant vitamin B 12 deficiency in the East-Hungarian region was 1.26/100 000 births, but the real frequency may be higher. Conslusions: Optimizing the cut off values of current screening parameters and measuring of methylmalonic acid and/or homocysteine in the dried blood spot, as a second tier test, can improve recognition rate of vitamin B 12 deficiency. Orv Hetil. 2017; 158(48): 1909-1918.
Severe Hypertriglyceridemia due to a novel p.Q240H mutation in the Lipoprotein Lipase gene.

PubMed

Soto, Angela Ganan; McIntyre, Adam; Agrawal, Sungeeta; Bialo, Shara R; Hegele, Robert A; Boney, Charlotte M

2015-09-04

Lipoprotein Lipase (LPL) deficiency is a rare autosomal recessive disorder with a heterogeneous clinical presentation. Several mutations in the LPL gene have been identified to cause decreased activity of the enzyme. An 11-week-old, exclusively breastfed male presented with coffee-ground emesis, melena, xanthomas, lipemia retinalis and chylomicronemia. Genomic DNA analysis identified lipoprotein lipase deficiency due to compound heterozygosity including a novel p.Q240H mutation in exon 5 of the lipoprotein lipase (LPL) gene. His severe hypertriglyceridemia, including xanthomas, resolved with dietary long-chain fat restriction. We describe a novel mutation of the LPL gene causing severe hypertriglyceridemia and report the response to treatment. A review of the current literature regarding LPL deficiency syndrome reveals a few potential new therapies under investigation.
Glycoprotein G deficient infectious laryngotracheitis virus is a candidate attenuated vaccine.

PubMed

Devlin, Joanne M; Browning, Glenn F; Hartley, Carol A; Gilkerson, James R

2007-05-04

Infectious laryngotracheitis virus (ILTV), an alphaherpesvirus, causes respiratory disease in chickens and is currently controlled by vaccination with conventionally attenuated virus strains. These vaccines have limitations because of residual pathogenicity and reversion to virulence, suggesting that a novel vaccine strain that lacks virulence gene(s) may enhance disease control. Glycoprotein G (gG) has recently been identified as a virulence factor in ILTV. In this study the immunogenicity and relative pathogenicity of gG deficient ILTV was investigated in SPF chickens. Birds vaccinated with gG deficient ILTV were protected against clinical signs of disease following challenge with virulent ILTV and gG deficient ILTV was also shown to be less pathogenic than currently available commercial vaccine strains. Thus gG deficient ILTV appears to have potential as a vaccine candidate.
Demarcation of potentially mineral-deficient areas in central and northern Namibia by means of natural classification systems.

PubMed

Grant, C C; Biggs, H C; Meissner, H H

1996-06-01

Mineral deficiencies that lead to production losses often occur concurrently with climatic and management changes. To diagnose these deficiencies in time to prevent production losses, long-term monitoring of mineral status is advisable. Different classification systems were examined to determine whether areas of possible mineral deficiencies could be identified, so that those which were promising could then be selected for further monitoring purposes. The classification systems addressed differences in soil, vegetation and geology, and were used to define the cattle-ranching areas in the central and northern districts of Namibia. Copper (Cu), Iron (Fe), zinc (Zn), manganese (Mn) and cobalt (Co) concentrations were determined in cattle livers collected at abattoirs. Pooled faecal grab samples and milk samples were collected by farmers, and used to determine phosphorus (P) and calcium (Ca), and iodine (I) status, respectively. Areas of low P concentrations could be identified by all classification systems. The lowest P concentrations were recorded in samples from the Kalahari-sand area, whereas faecal samples collected from cattle on farms in the more arid areas, where the harder soils are mostly found, rarely showed low P concentrations. In the north of the country, low iodine levels were found in milk samples collected from cows grazing on farms in the northern Kalahari broad-leaved woodland. Areas supporting animals with marginal Cu status, could be effectively identified by the detailed soil-classification system of irrigation potential. Copper concentrations were lowest in areas of arid soils, but no indication of Co, Fe, Zn, or Mn deficiencies were found. For most minerals, the geological classification was the best single indicator of areas of lower concentrations. Significant monthly variation for all minerals could also be detected within the classification system. It is concluded that specific classification systems can be useful as indicators of areas with lower mineral concentrations or possible deficiencies.
Prevalence of vitamin D deficiency and its associated factors in three regions of Saudi Arabia

PubMed Central

Kaddam, Ibrahim M.; Al-Shaikh, Adnan M.; Abaalkhail, Bahaa A.; Asseri, Khalid S.; Al-Saleh, Yousef M.; Al-Qarni, Ali A.; Al-Shuaibi, Ahmed M.; Tamimi, Waleed G.; Mukhtar, Abdelmoneim M.

2017-01-01

Objectives: To measure prevalence of vitamin D deficiency in Saudi Arabia, unveil the life style, nutritional habits and status, as well as identify the potential risk factors. Method: A school-based survey targeting Saudi school students and employees was conducted during the period from 2013 to 2014 using multistage cluster random sample in Central, Western and Eastern regions. The prevalence of vitamin D deficiency and difference between various population subgroups were calculated. Logistic regression analysis was used to determine the predictors of potential risk factors. Results: Prevalence of vitamin D deficiency was 49.5% in students and 44% in employees. Life style was not adequate to protect against vitamin D depletion. Unhealthy nutritional habits were widespread, some manifested in childhood while others manifested later in life. Living in the Eastern region, females, 16-19 years of age, low economic class, obese and lack of omega 3 supplements were risk factors in students. Employees living in the Eastern region, females, middle-income class, carbonated soft drink consumers, and lack of multivitamin supplements were at higher risk. Conclusion: There is a need for a health awareness program using evidence-based recommendations. Screening for early detection and correction of the condition should be proposed to be part of the national health strategy. There is need for identifying the burden of vitamin D deficiency on other diseases to control and improve the prognosis of these conditions. PMID:28397944

Towards a general framework for predicting threat status of data-deficient species from phylogenetic, spatial and environmental information.

PubMed

Jetz, Walter; Freckleton, Robert P

2015-02-19

In taxon-wide assessments of threat status many species remain not included owing to lack of data. Here, we present a novel spatial-phylogenetic statistical framework that uses a small set of readily available or derivable characteristics, including phylogenetically imputed body mass and remotely sensed human encroachment, to provide initial baseline predictions of threat status for data-deficient species. Applied to assessed mammal species worldwide, the approach effectively identifies threatened species and predicts the geographical variation in threat. For the 483 data-deficient species, the models predict highly elevated threat, with 69% 'at-risk' species in this set, compared with 22% among assessed species. This results in 331 additional potentially threatened mammals, with elevated conservation importance in rodents, bats and shrews, and countries like Colombia, Sulawesi and the Philippines. These findings demonstrate the future potential for combining phylogenies and remotely sensed data with species distributions to identify species and regions of conservation concern. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

PubMed Central

2014-01-01

Background Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. Results We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. Conclusion Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required. PMID:24484525
Mutations in Nicotinamide Nucleotide Transhydrogenase (NNT) cause familial glucocorticoid deficiency

PubMed Central

Meimaridou, Eirini; Kowalczyk, Julia; Guasti, Leonardo; Hughes, Claire R.; Wagner, Florian; Frommolt, Peter; Nürnberg, Peter; Mann, Nicholas P.; Banerjee, Ritwik; Saka, H. Nurcin; Chapple, J. Paul; King, Peter J.; Clark, Adrian J.L.; Metherell, Louise A.

2012-01-01

Using targeted exome sequencing we identified mutations in NNT, an antioxidant defence gene, in patients with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased ROS levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands. PMID:22634753
GC-MS analysis of headspace and liquid extracts for metabolomic differentiation of citrus Huanglongbing and zinc deficiency in leaves of 'Valencia' sweet orange from commercial groves.

PubMed

Cevallos-Cevallos, Juan Manuel; García-Torres, Rosalía; Etxeberria, Edgardo; Reyes-De-Corcuera, José Ignacio

2011-01-01

Citrus Huanglongbing (HLB) is considered the most destructive citrus disease worldwide. Symptoms-based detection of HLB is difficult due to similarities with zinc deficiency. To find metabolic differences between leaves from HLB-infected, zinc-deficient, and healthy 'Valencia' orange trees by using GC-MS based metabolomics. Analysis based on GC-MS methods for untargeted metabolite analysis of citrus leaves was developed and optimized. Sample extracts from healthy, zinc deficient, or HLB-infected sweet orange leaves were submitted to headspace solid phase micro-extraction (SPME) and derivatization treatments prior to GC-MS analysis. Principal components analysis achieved correct classification of all the derivatized liquid extracts. Analysis of variance revealed 6 possible biomarkers for HLB, of which 5 were identified as proline, β-elemene, (-)trans- caryophyllene, and α-humulene. Significant (P < 0.05) differences in oxo-butanedioic acid, arabitol, and neo-inositol were exclusively detected in samples from plants with zinc deficiency. Levels of isocaryophyllen, α-selinene, β-selinene, and fructose were significantly (P < 0.05) different in healthy leaves only. Results suggest the potential of using identified HLB biomarkers for rapid differentiation of HLB from zinc deficiency. Copyright © 2010 John Wiley & Sons, Ltd.
Functional redundancy of mitochondrial enoyl-CoA isomerases in the oxidation of unsaturated fatty acids.

PubMed

van Weeghel, Michel; te Brinke, Heleen; van Lenthe, Henk; Kulik, Wim; Minkler, Paul E; Stoll, Maria S K; Sass, Jörn Oliver; Janssen, Uwe; Stoffel, Wilhelm; Schwab, K Otfried; Wanders, Ronald J A; Hoppel, Charles L; Houten, Sander M

2012-10-01

Mitochondrial enoyl-CoA isomerase (ECI1) is an auxiliary enzyme involved in unsaturated fatty acid oxidation. In contrast to most of the other enzymes involved in fatty acid oxidation, a deficiency of ECI1 has yet to be identified in humans. We used wild-type (WT) and Eci1-deficient knockout (KO) mice to explore a potential presentation of human ECI1 deficiency. Upon food withdrawal, Eci1-deficient mice displayed normal blood β-hydroxybutyrate levels (WT 1.09 mM vs. KO 1.10 mM), a trend to lower blood glucose levels (WT 4.58 mM vs. KO 3.87 mM, P=0.09) and elevated blood levels of unsaturated acylcarnitines, in particular C12:1 acylcarnitine (WT 0.03 μM vs. KO 0.09 μM, P<0.01). Feeding an olive oil-rich diet induced an even greater increase in C12:1 acylcarnitine levels (WT 0.01 μM vs. KO 0.04 μM, P<0.01). Overall, the phenotypic presentation of Eci1-deficient mice is mild, possibly caused by the presence of a second enoyl-CoA isomerase (Eci2) in mitochondria. Knockdown of Eci2 in Eci1-deficient fibroblasts caused a more pronounced accumulation of C12:1 acylcarnitine on incubation with unsaturated fatty acids (12-fold, P<0.05). We conclude that Eci2 compensates for Eci1 deficiency explaining the mild phenotype of Eci1-deficient mice. Hypoglycemia and accumulation of C12:1 acylcarnitine might be diagnostic markers to identify ECI1 deficiency in humans.
Increased red cell turnover in a line of CD22-deficient mice is caused by Gpi1c: a model for hereditary haemolytic anaemia.

PubMed

Walker, Jennifer A; Hall, Andrew M; Kotsopoulou, Ekaterini; Espeli, Marion; Nitschke, Lars; Barker, Robert N; Lyons, Paul A; Smith, Kenneth G C

2012-12-01

CD22, an inhibitory co-receptor of the BCR, has been identified as a potential candidate gene for the development of autoimmune haemolytic anaemia in mice. In this study, we have examined Cd22(tm1Msn) CD22-deficient mice and identified an increase in RBC turnover and stress erythropoiesis, which might be consistent with haemolysis. We then, however, eliminated CD22 deficiency as the cause of accelerated RBC turnover and established that enhanced RBC turnover occurs independently of B cells and anti-RBC autoanti-bodies. Accelerated RBC turnover in this particular strain of CD22-deficient mice is red cell intrinsic and appears to be the consequence of a defective allele of glucose phosphate isomerase, Gpi1(c). This form of Gpi1 was originally derived from wild mice and results in a substantial reduction in enzyme activity. We have identified the polymorphism that causes impaired catalytic activity in the Gpi1(c) allele, and biochemically confirmed an approximate 75% reduction of GPI1 activity in Cd22(-/-) RBCs. The Cd22(-/-).Gpi1(c) congenic mouse provides a novel animal model of GPI1-deficiency, which is one of the most common causes of chronic non-spherocytic haemolytic anaemia in humans. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Measurements of vitamin B12 in human blood serum using resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Tsiminis, G.; Schartner, E. P.; Brooks, J. L.; Hutchinson, M. R.

2016-12-01

Vitamin B12 (cobalamin and its derivatives) deficiency has been identified as a potential modifiable risk factor for dementia and Alzheimer's disease. Chronic deficiency of vitamin B12 has been significantly associated with an increased risk of cognitive decline. An effective and efficient method for measuring vitamin B12 concentration in human blood would enable ongoing tracking and assessment of this potential modifiable risk factor. In this work we present an optical sensor based on resonance Raman spectroscopy for rapid measurements of vitamin B12 in human blood serum. The measurement takes less than a minute and requires minimum preparation (centrifuging) of the collected blood samples.
GC-TOF/MS-based metabolomic profiling of estrogen deficiency-induced obesity in ovariectomized rats

PubMed Central

Ma, Bo; Zhang, Qi; Wang, Guang-ji; A, Ji-ye; Wu, Di; Liu, Ying; Cao, Bei; Liu, Lin-sheng; Hu, Ying-ying; Wang, Yong-lu; Zheng, Ya-ya

2011-01-01

Aim: To explore the alteration of endogenous metabolites and identify potential biomarkers using metabolomic profiling with gas chromatography coupled a time-of-flight mass analyzer (GC/TOF-MS) in a rat model of estrogen-deficiency-induced obesity. Methods: Twelve female Sprague-Dawley rats six month of age were either sham-operated or ovariectomized (OVX). Rat blood was collected, and serum was analyzed for biomarkers using standard colorimetric methods with commercial assay kits and a metabolomic approach with GC/TOF-MS. The data were analyzed using multivariate statistical techniques. Results: A high body weight and body mass index inversely correlated with serum estradiol (E2) in the OVX rats compared to the sham rats. Estrogen deficiency also significantly increased serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Utilizing GC/TOF-MS-based metabolomic analysis and the partial least-squares discriminant analysis, the OVX samples were discriminated from the shams. Elevated levels of cholesterol, glycerol, glucose, arachidonic acid, glutamic acid, glycine, and cystine and reduced alanine levels were observed. Serum glucose metabolism, energy metabolism, lipid metabolism, and amino acid metabolism were involved in estrogen-deficiency-induced obesity in OVX rats. Conclusion: The series of potential biomarkers identified in the present study provided fingerprints of rat metabolomic changes during obesity and an overview of multiple metabolic pathways during the progression of obesity involving glucose metabolism, lipid metabolism, and amino acid metabolism. PMID:21293480
Vitamin D deficiency and pregnancy rates in women undergoing single embryo, blastocyst stage, transfer (SET) for IVF/ICSI.

PubMed

Polyzos, Nikolaos P; Anckaert, Ellen; Guzman, Luis; Schiettecatte, Johan; Van Landuyt, Lisbet; Camus, Michel; Smitz, Johan; Tournaye, Herman

2014-09-01

What is the influence of vitamin D deficiency on pregnancy rates among women undergoing IVF/ICSI and Day 5 (blastocyst stage) single embryo transfer (SET)? Vitamin D deficiency results in significantly lower pregnancy rates in women undergoing single blastocyst transfer. Preliminary experiments have identified the presence of vitamin D receptors in the female reproductive system. However, results regarding the effect of vitamin D deficiency on clinical outcomes are conflicting. None of the previous studies adopted a SET strategy. Serum vitamin D concentration was measured retrospectively in patients who underwent SET on Day 5. Overall 368 consecutive infertile women treated within a period of 15 months were included in the study. All patients underwent ovarian stimulation for IVF/ICSI and Day 5 SET. Serum samples were obtained 7 days prior to embryo transfer and stored frozen at -20°C. Samples were collectively analyzed for their 25-OH vitamin D content. Vitamin D deficiency was defined as serum 25-OH vitamin D levels <20 ng/ml in accordance with the Institute of Medicine and the Endocrine Society clinical practice guidelines. Clinical pregnancy rates were significantly lower in women with vitamin D deficiency compared with those with higher vitamin D values (41 versus 54%, P = 0.015).Logistic regression analysis was performed to identify whether vitamin D deficiency is independently associated with clinical pregnancy rates after controlling for 16 potential confounding factors. According to our results vitamin D deficiency was independently associated with lower clinical pregnancy rates, odds ratios [ORs (95% confidence interval (CI) 0.61 (0.39-0.95)] for vitamin D deficiency (deficient versus non-deficient women), P = 0.030. Finally, even when restricting our analysis to women undergoing elective SET (274 patients), vitamin D deficiency was again independently associated with pregnancy rates [OR (95% CI) 0.56 (0.33-0.93), P = 0.024]. Our results refer only to patients undergoing Day 5 SET. Although vitamin D deficiency appears to compromise pregnancy rates in this population, no guidance can be provided regarding a potential relationship between vitamin D deficiency and ovarian reserve or response to ovarian stimulation. Vitamin D deficiency impairs pregnancy rates in women undergoing single blastocyst transfer. Future prospective confirmatory studies are needed to validate our results and examine the exact underlying mechanism by which vitamin D levels may impair pregnancy rates in infertile women undergoing IVF/ICSI. None declared. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers

PubMed Central

Hocke, Sandra; Guo, Yang; Job, Albert; Orth, Michael; Ziesch, Andreas; Lauber, Kirsten; De Toni, Enrico N; Gress, Thomas M.; Herbst, Andreas; Göke, Burkhard; Gallmeier, Eike

2016-01-01

The phosphoinositide 3-kinase-related kinase ATR represents a central checkpoint regulator and mediator of DNA-repair. Its inhibition selectively eliminates certain subsets of cancer cells in various tumor types, but the underlying genetic determinants remain enigmatic. Here, we applied a synthetic lethal screen directed against 288 DNA-repair genes using the well-defined ATR knock-in model of DLD1 colorectal cancer cells to identify potential DNA-repair defects mediating these effects. We identified a set of DNA-repair proteins, whose knockdown selectively killed ATR-deficient cancer cells. From this set, we further investigated the profound synthetic lethal interaction between ATR and POLD1. ATR-dependent POLD1 knockdown-induced cell killing was reproducible pharmacologically in POLD1-depleted DLD1 cells and a panel of other colorectal cancer cell lines by using chemical inhibitors of ATR or its major effector kinase CHK1. Mechanistically, POLD1 depletion in ATR-deficient cells caused caspase-dependent apoptosis without preceding cell cycle arrest and increased DNA-damage along with impaired DNA-repair. Our data could have clinical implications regarding tumor genotype-based cancer therapy, as inactivating POLD1 mutations have recently been identified in small subsets of colorectal and endometrial cancers. POLD1 deficiency might thus represent a predictive marker for treatment response towards ATR- or CHK1-inhibitors that are currently tested in clinical trials. PMID:26755646
Multiplex primer extension reaction screening and oxidative challenge of glucose-6-phosphate dehydrogenase mutants in hemizygous and heterozygous subjects.

PubMed

Ko, Chun Hay; Yung, Edmund; Li, Karen; Li, Chung Leung; Ng, Pak Cheung; Fung, Kwok Pui; Wong, Raymond Pui-On; Chui, Kit Man; Gu, Goldie Jia-Shi; Fok, Tai Fai

2006-01-01

The primary objective of our study was to provide a simple and reliable assay for identifying the majority of G6PD genetic variants in the Chinese population. We optimized the multiplex primer extension reaction (MPER) assay for simultaneous screening of 14-point mutations in 98 G6PD-deficient subjects. Our data demonstrated that this method is precise, cost-effective and has successfully identified mutations in 97 out of 98 subjects, including all heterozygous mutants. We also detected a relatively high incidence (12.3%) of c.871G > A, and all of them harbored the silent mutation c.1311C > T. Apart from the screening program, the pharmacogenetic relationship between G6PD level and residual reduced glutathione (GSH) level was studied upon oxidative challenge by alpha-naphthol. The GSH levels were correlated with their status of G6PD deficiency, but no significant difference was observed between individual G6PD-deficient groups. Our data demonstrated the potentials of the MPER assay for characterization of G6PD deficiency and other genetic diseases.
Mitochondrial disease associated with complex I (NADH-CoQ oxidoreductase) deficiency.

PubMed

Scheffler, Immo E

2015-05-01

Mitochondrial diseases due to a reduced capacity for oxidative phosphorylation were first identified more than 20 years ago, and their incidence is now recognized to be quite significant. In a large proportion of cases the problem can be traced to a complex I (NADH-CoQ oxidoreductase) deficiency (Phenotype MIM #252010). Because the complex consists of 44 subunits, there are many potential targets for pathogenic mutations, both on the nuclear and mitochondrial genomes. Surprisingly, however, almost half of the complex I deficiencies are due to defects in as yet unidentified genes that encode proteins other than the structural proteins of the complex. This review attempts to summarize what we know about the molecular basis of complex I deficiencies: mutations in the known structural genes, and mutations in an increasing number of genes encoding "assembly factors", that is, proteins required for the biogenesis of a functional complex I that are not found in the final complex I. More such genes must be identified before definitive genetic counselling can be applied in all cases of affected families.
Factor VII deficiency: a novel missense variant and genotype-phenotype correlation in patients from Southern Italy.

PubMed

Tiscia, Giovanni; Favuzzi, Giovanni; Chinni, Elena; Colaizzo, Donatella; Fischetti, Lucia; Intrieri, Mariano; Margaglione, Maurizio; Grandone, Elvira

2017-01-01

This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients.
Eight novel F13A1 gene missense mutations in patients with mild FXIII deficiency: in silico analysis suggests changes in FXIII-A subunit structure/function.

PubMed

Biswas, Arijit; Ivaskevicius, Vytautas; Thomas, Anne; Varvenne, Michael; Brand, Brigitte; Rott, Hannelore; Haussels, Iris; Ruehl, Heiko; Scholz, Ute; Klamroth, Robert; Oldenburg, Johannes

2014-10-01

Mild FXIII deficiency is an under-diagnosed disorder because the carriers of this deficiency are often asymptomatic and reveal a phenotype only under special circumstances like surgery or induced trauma. Mutational reports from this type of deficiency have been rare. In this study, we present the phenotypic and genotypic data of nine patients showing mild FXIII-A deficiency caused by eight novel heterozygous missense mutations (Pro166Leu, Arg171Gln, His342Tyr, Gln415Arg, Leu529Pro, Gln601Lys, Arg703Gln and Arg715Gly) in the F13A1 gene. None of these variants were seen in 200 healthy controls. In silico structural analysis of the local wild-type protein structures (activated and non-activated) from X-ray crystallographic models downloaded from the protein databank identified potential structural/functional effects for the identified mutations. The missense mutations in the core domain are suggested to be directly influencing the catalytic triad. Mutations on other domains might influence other critical factors such as activation peptide cleavage or the barrel domain integrity. In vitro expression and subsequent biochemical studies in the future will be able to confirm the pathophysiological mechanisms proposed for the mutations in this article.
[Detection and application of PIS genetic deficiency gene in dairy goat].

PubMed

Yang, Bo; Jia, Li-Li; Zhao, De-Chao; Meng, Li-Yun; Liu, Xue-Feng; Zhang, Yan-Jun; Zhang, Wen-Guang; Li, Jin-Quan

2012-07-01

The purpose of this study was to develop a molecular method for detecting polled intersex syndrome (PIS) genetic deficiency gene in dairy goat. Three pairs of primers, PIS-, PIS+, and NEI were designed based on PIS gene sequence (AF404302) to identify the PIS genetic deficiency genotype. For the normal phenotype, the fragments of 141 and 300 bp were obtained for the genotype PIS-PIS-, and 141, 449, and 300 bp for the genotype PIS-PIS+. For the PIS goat with the genotype PIS+PIS+, 449 and 300 bp were obtained. Two hundred and twenty-four dairy goats in one population were tested based on this method. The results showed that there were 150 PIS-PIS+, 70 PIS -PIS-, and 4 PIS+PIS+. The genotype frequency of PIS-PIS+ was 66.9%, and the gene frequency of PIS+ was 35.3% in the population. Therefore, the frequency of PIS offspring was over 12%. This study developed a method to detect PIS genetic deficiency dairy goat. The method could identify buck genotype accurately to avoid the occurrence of PIS genetic deficiency. The ease and accuracy show a strong potential of the method for use in marker assisted selection of dairy goats and healthy development of dairy goat industry.
Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines.

PubMed

Yamamoto, Kimiyo N; Hirota, Kouji; Kono, Koichi; Takeda, Shunichi; Sakamuru, Srilatha; Xia, Menghang; Huang, Ruili; Austin, Christopher P; Witt, Kristine L; Tice, Raymond R

2011-08-01

Included among the quantitative high throughput screens (qHTS) conducted in support of the US Tox21 program are those being evaluated for the detection of genotoxic compounds. One such screen is based on the induction of increased cytotoxicity in seven isogenic chicken DT40 cell lines deficient in DNA repair pathways compared to the parental DNA repair-proficient cell line. To characterize the utility of this approach for detecting genotoxic compounds and identifying the type(s) of DNA damage induced, we evaluated nine of 42 compounds identified as positive for differential cytotoxicity in qHTS (actinomycin D, adriamycin, alachlor, benzotrichloride, diglycidyl resorcinol ether, lovastatin, melphalan, trans-1,4-dichloro-2-butene, tris(2,3-epoxypropyl)isocyanurate) and one non-cytotoxic genotoxic compound (2-aminothiamine) for (1) clastogenicity in mutant and wild-type cells; (2) the comparative induction of γH2AX positive foci by melphalan; (3) the extent to which a 72-hr exposure duration increased assay sensitivity or specificity; (4) the use of 10 additional DT40 DNA repair-deficient cell lines to better analyze the type(s) of DNA damage induced; and (5) the involvement of reactive oxygen species in the induction of DNA damage. All compounds but lovastatin and 2-aminothiamine were more clastogenic in at least one DNA repair-deficient cell line than the wild-type cells. The differential responses across the various DNA repair-deficient cell lines provided information on the type(s) of DNA damage induced. The results demonstrate the utility of this DT40 screen for detecting genotoxic compounds, for characterizing the nature of the DNA damage, and potentially for analyzing mechanisms of mutagenesis. Copyright © 2011 Wiley-Liss, Inc.
Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repair-deficient chicken DT40 cell lines

PubMed Central

Yamamoto, Kimiyo N.; Hirota, Kouji; Kono, Koichi; Takeda, Shunichi; Sakamuru, Srilatha; Xia, Menghang; Huang, Ruili; Austin, Christopher P.; Witt, Kristine L.; Tice, Raymond R.

2012-01-01

Included among the quantitative high throughput screens (qHTS) conducted in support of the U.S. Tox21 program are those being evaluated for the detection of genotoxic compounds. One such screen is based on the induction of increased cytotoxicity in 7 isogenic chicken DT40 cell lines deficient in DNA repair pathways compared to the parental DNA repair-proficient cell line. To characterize the utility of this approach for detecting genotoxic compounds and identifying the type(s) of DNA damage induced, we evaluated nine of 42 compounds identified as positive for differential cytotoxicity in qHTS (actinomycin D, adriamycin, alachlor, benzotrichloride, diglycidyl resorcinol ether, lovastatin, melphalan, trans-1,4-dichloro-2-butene, tris(2,3-epoxypropyl)isocyanurate) and one non-cytotoxic genotoxic compound (2-aminothiamine) for (1) clastogenicity in mutant and wild-type cells; (2) the comparative induction of γH2AX positive foci by melphalan; (3) the extent to which a 72-hr exposure duration increased assay sensitivity or specificity; (4) the use of 10 additional DT40 DNA repair-deficient cell lines to better analyze the type(s) of DNA damage induced; and (5) the involvement of reactive oxygen species in the induction of DNA damage. All compounds but lovastatin and 2-aminothiamine were more clastogenic in at least one DNA repair-deficient cell line than the wild-type cells. The differential responses across the various DNA repair-deficient cell lines provided information on the type(s) of DNA damage induced. The results demonstrate the utility of this DT40 screen for detecting genotoxic compounds, for characterizing the nature of the DNA damage, and potentially for analyzing mechanisms of mutagenesis. PMID:21538559
Deficiencies of product labeling directions for the preparation of radiopharmaceuticals.

PubMed

Hung, Joseph C; Ponto, James A; Gadient, Katie R; Frie, Julia A; Aksamit, Carolyn M; Enquist, Cassandra L; Carrels, Katie E

2004-01-01

To identify potential deficiencies in product labeling (package insert) instructions for the preparation of radiopharmaceuticals. Preparation instructions, which include both reconstitution and quality control (QC) directions, as stated in the package inserts were evaluated for all commercially available reconstituted radiopharmaceuticals. Reviews of the package inserts were initially performed by each author, and then all identified deficiencies were compiled and evaluated by all authors. The preparation scenario for each package insert evaluated was based on a centralized nuclear pharmacy operation assuming typical support personnel, standard operating equipment, and workload. The instructions as stated in each package insert for the preparation (including QC) were rated as inadequate if a satisfactory preparation could not be prepared by a nuclear pharmacist or physician when instructions were followed exactly. Identified deficiencies in package insert instructions for the preparation of radiopharmaceuticals fell into the following five categories: (1) absent or incomplete directions (especially with regard to QC procedures); (2) restrictive directions (e.g., specific requirement to use designated needles, chromatography solvents, counting devices), (3) inconsistent directions (e.g., different reconstituted volumes for the same final drug product, unworkable expiration times); (4) impractical directions (e.g., unrealistically low reconstituted activity limits, dangerously high number of radiolabeled particles); and (5) vague directions (e.g., use of the words "should," "may," "recommend"). Manufacturers' directions for the preparation of radiopharmaceuticals often contain deficiencies and should be viewed as standard guidance rather than as requirements. Just as physicians are permitted to use U.S. Food and Drug Administration (FDA)-approved drugs for off-label indications, nuclear pharmacists should be allowed to use alternative methods for preparing radiopharmaceuticals, provided those methods have been validated to be as good as the stated directions and that the nuclear pharmacists do not engage in activities that fall outside the normal practice of pharmacy. Manufacturers, FDA, nuclear pharmacists, and nuclear physicians should work together to address identified deficiencies in package insert directions.
Systems biology study of mucopolysaccharidosis using a human metabolic reconstruction network.

PubMed

Salazar, Diego A; Rodríguez-López, Alexander; Herreño, Angélica; Barbosa, Hector; Herrera, Juliana; Ardila, Andrea; Barreto, George E; González, Janneth; Alméciga-Díaz, Carlos J

2016-02-01

Mucopolysaccharidosis (MPS) is a group of lysosomal storage diseases (LSD), characterized by the deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans (GAG). This deficiency leads to the lysosomal accumulation of partially degraded GAG. Nevertheless, deficiency of a single lysosomal enzyme has been associated with impairment in other cell mechanism, such as apoptosis and redox balance. Although GAG analysis represents the main biomarker for MPS diagnosis, it has several limitations that can lead to a misdiagnosis, whereby the identification of new biomarkers represents an important issue for MPS. In this study, we used a system biology approach, through the use of a genome-scale human metabolic reconstruction to understand the effect of metabolism alterations in cell homeostasis and to identify potential new biomarkers in MPS. In-silico MPS models were generated by silencing of MPS-related enzymes, and were analyzed through a flux balance and variability analysis. We found that MPS models used approximately 2286 reactions to satisfy the objective function. Impaired reactions were mainly involved in cellular respiration, mitochondrial process, amino acid and lipid metabolism, and ion exchange. Metabolic changes were similar for MPS I and II, and MPS III A to C; while the remaining MPS showed unique metabolic profiles. Eight and thirteen potential high-confidence biomarkers were identified for MPS IVB and VII, respectively, which were associated with the secondary pathologic process of LSD. In vivo evaluation of predicted intermediate confidence biomarkers (β-hexosaminidase and β-glucoronidase) for MPS IVA and VI correlated with the in-silico prediction. These results show the potential of a computational human metabolic reconstruction to understand the molecular mechanisms this group of diseases, which can be used to identify new biomarkers for MPS. Copyright © 2015. Published by Elsevier Inc.
COUP-TFII regulates satellite cell function and muscular dystrophy.

PubMed

Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer

2016-10-03

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease's pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII-overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

Should blood donors be routinely screened for glucose-6-phosphate dehydrogenase deficiency? A systematic review of clinical studies focusing on patients transfused with glucose-6-phosphate dehydrogenase-deficient red cells.

PubMed

Renzaho, Andre M N; Husser, Eliette; Polonsky, Michael

2014-01-01

The risk factors associated with the use of glucose-6-phosphate dehydrogenase (G6PD)-deficient blood in transfusion have not yet been well established. Therefore, the aim of this review was to evaluate whether whole blood from healthy G6PD-deficient donors is safe to use for transfusion. The study undertook a systematic review of English articles indexed in COCHRANE, MEDLINE, EMBASE, and CINHAL, with no date restriction up to March 2013, as well as those included in articles' reference lists and those included in Google Scholar. Inclusion criteria required that studies be randomized controlled trials, case controls, case reports, or prospective clinical series. Data were extracted following the Preferred Reporting Items for Systematic Reviews using a previously piloted form, which included fields for study design, population under study, sample size, study results, limitations, conclusions, and recommendations. The initial search identified 663 potentially relevant articles, of which only 13 studies met the inclusion criteria. The reported effects of G6PD-deficient transfused blood on neonates and children appear to be more deleterious than effects reported on adult patients. In most cases, the rise of total serum bilirubin was abnormal in infants transfused with G6PD-deficient blood from 6 hours up to 60 hours after transfusion. All studies on neonates and children, except one, recommended a routine screening for G6PD deficiency for this at-risk subpopulation because their immature hepatic function potentially makes them less able to handle any excess bilirubin load. It is difficult to make firm clinical conclusions and recommendations given the equivocal results, the lack of standardized evaluation methods to categorize red blood cell units as G6PD deficient (some of which are questionable), and the limited methodological quality and low quality of evidence. Notwithstanding these limitations, based on our review of the available literature, there is little to suggest that G6PD-deficient individuals should be excluded from donating red blood cells, although transfusions of such blood may potentially have negative impacts on premature neonates or patients who need repeated transfusions, and thus, for this group, screening for G6PD deficiency may be appropriate. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.
Assessment of the availability of technology for trauma care in India.

PubMed

Shah, Mihir Tejanshu; Joshipura, Manjul; Singleton, Jered; LaBarre, Paul; Desai, Hem; Sharma, Eliza; Mock, Charles

2015-02-01

We sought to assess the status of availability of technology for trauma care in a state in India and to identify factors contributing to both adequate levels of availability and to deficiencies. We also sought to identify potential solutions to deficiencies in terms of health system management and product development. Thirty-two technology-related items were selected from the World Health Organization's Guidelines for Essential Trauma Care. The status of these items was assessed at 43 small and large hospitals in Gujarat State. Site visits utilized direct inspection and interviews with administrative, clinical, and bioengineering staff. Many specific individual items could be better supplied, including many that were very low cost (e.g., chest tubes). Many deficiencies arose because of mismatch of resources, such as availability of equipment in the absence of personnel trained to use it. Several locally manufactured items were fairly well supplied: pulse oximetry, image intensification, and X-ray machines. Ventilators were often deficient because of inadequate numbers of units and frequent breakdowns. Availability of a range of lower-cost items could be improved by better organization and planning, such as: better procurement and stock management; eliminating mismatch of resources, including optimizing training for use of existing resources; and by strengthening service contracts and in-house repair capabilities. From a product development viewpoint, there is a need for lower cost, more durable, and easier to repair ventilators. Promoting increased capacity for local manufacturing should also be considered as a potential method to decrease cost and increase availability of a range of equipment.
Neurofibromin Deficiency-Associated Transcriptional Dysregulation Suggests a Novel Therapy for Tibial Pseudoarthrosis in NF1

PubMed Central

Paria, Nandina; Cho, Tae-Joon; Choi, In Ho; Kamiya, Nobuhiro; Kayembe, Kay; Mao, Rong; Margraf, Rebecca L.; Obermosser, Gerlinde; Oxendine, Ila; Sant, David W.; Song, Mi Hyun; Stevenson, David A.; Viskochil, David H.; Wise, Carol A.; Kim, Harry K.W.; Rios, Jonathan J

2014-01-01

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic bi-allelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinosital-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant over-expression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing. PMID:24932921
Vitamin D deficiency is common among adults in Wallonia (Belgium, 51°30' North): findings from the Nutrition, Environment and Cardio-Vascular Health study.

PubMed

Hoge, Axelle; Donneau, Anne-Françoise; Streel, Sylvie; Kolh, Philippe; Chapelle, Jean-Paul; Albert, Adelin; Cavalier, Etienne; Guillaume, Michèle

2015-08-01

Data on the vitamin D status of the population of Wallonia (Belgium, 51°30' North) are scarce. This study was carried out to estimate vitamin D deficiency, identify potential determinants, and analyze their relationship with vitamin D supplementation. We tested the hypothesis that vitamin D deficiency is common in the general population, particularly among subjects without supplementation. Vitamin D deficiency was defined as a serum level of 25-hydroxyvitamin D (25(OH)D) concentration less than 50nmol/L. Data were analyzed from 915 participants of the Nutrition, Environment and Cardio-Vascular Health cross-sectional survey. The median (interquartile range) 25(OH)D level was 53.1 (37.8-69.9) nmol/L, and 44.7% of the subjects were vitamin D deficient. Subjects without vitamin D supplementation were more concerned by vitamin D deficiency than those with supplementation (odds ratio [OR], 3.35; P < .0001). From a multivariate standpoint, the potential determinants of vitamin D deficiency among subjects without vitamin D supplementation were season, specifically spring and winter (OR, 7.36 and 6.44, respectively), obesity (OR, 2.19), low household income (OR, 1.73), and lack of solarium use (OR, 1.79). For subjects with supplementation, the only determinant observed for vitamin D deficiency was obesity (OR, 5.00). This work evidenced the high prevalence of 25(OH)D deficiency in the general population, especially among nonsupplemented subjects with obesity, low household income, and/or lack of light. Vitamin D supplementation looks effective in our population, especially via a stabilization of vitamin D coverage throughout the seasons. The best dietary strategy to achieve optimal 25(OH)D concentrations all year round in the general population requires more research. Copyright © 2015 Elsevier Inc. All rights reserved.
Mutational analysis of GALT gene in Greek patients with galactosaemia: identification of two novel mutations and clinical evaluation.

PubMed

Schulpis, Kleopatra H; Thodi, Georgia; Iakovou, Konstantinos; Chatzidaki, Maria; Dotsikas, Yannis; Molou, Elina; Triantafylli, Olga; Loukas, Yannis L

2017-10-01

Classical galactosaemia is an inborn error of metabolism due to the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). The aim of the study was to identify the underlying mutations in Greek patients with GALT deficiency and evaluate their psychomotor and speech development. Patients with GALT deficiency (n = 17) were picked up through neonatal screening. Mutational analysis was conducted via Sanger sequencing, while in silico analysis was used in the cases of novel missense mutations. Psychomotor speech development tests were utilized for the clinical evaluation of the patients. Eleven different mutations in the GALT gene were detected in the patient cohort, including two novel ones. The most frequent mutation was p.Q188R (c.563 A > G). As for the novel mutations, p.M298I (c.894 G > A) was identified in four out of 32 independent alleles, while p.P115S (c.343 C > T) was identified once. Psychomotor evaluation revealed that most of the patients were found in the borderline area (Peabody test), while only two had speech delay problems. The WISK test revealed three patients at borderline limits and two were at lower than normal limits. The mutational spectrum of the GALT gene in Greek patients is presented for the first time. The mutation p.Q188R is the most frequent among Greek patients. Two novel mutations were identified and their potential pathogenicity was estimated. Regarding the phenotypic characteristics, psychomotor disturbances and speech delay were mainly observed among GALT-deficient patients.
A national assessment of underground natural gas storage: identifying wells with designs likely vulnerable to a single-point-of-failure

NASA Astrophysics Data System (ADS)

Michanowicz, Drew R.; Buonocore, Jonathan J.; Rowland, Sebastian T.; Konschnik, Katherine E.; Goho, Shaun A.; Bernstein, Aaron S.

2017-05-01

The leak of processed natural gas (PNG) from October 2015 to February 2016 from the Aliso Canyon storage facility, near Los Angeles, California, was the largest single accidental release of greenhouse gases in US history. The Interagency Task Force on Natural Gas Storage Safety and California regulators recently recommended operators phase out single-point-of-failure (SPF) well designs. Here, we develop a national dataset of UGS well activity in the continental US to assess regulatory data availability and uncertainty, and to assess the prevalence of certain well design deficiencies including single-point-of-failure designs. We identified 14 138 active UGS wells associated with 317 active UGS facilities in 29 states using regulatory and company data. State-level wellbore datasets contained numerous reporting inconsistencies that limited data concatenation. We identified 2715 active UGS wells across 160 facilities that, like the failed well at Aliso Canyon, predated the storage facility, and therefore were not originally designed for gas storage. The majority (88%) of these repurposed wells are located in OH, MI, PA, NY, and WV. Repurposed wells have a median age of 74 years, and the 2694 repurposed wells constructed prior to 1979 are particularly likely to exhibit design-related deficiencies. An estimated 210 active repurposed wells were constructed before 1917—before cement zonal isolation methods were utilized. These wells are located in OH, PA, NY, and WV and represent the highest priority related to potential design deficiencies that could lead to containment loss. This national baseline assessment identifies regulatory data uncertainties, highlights a potentially widespread vulnerability of the natural gas supply chain, and can aid in prioritization and oversight for high-risk wells and facilities.
Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity.

PubMed

Dehghani, Mohammad Reza; Mehrjardi, Mohammad Yahya Vahidi; Dilaver, Nafi; Tajamolian, Masoud; Enayati, Samaneh; Ebrahimi, Pirooz; Amoli, Mahsa M; Farooqi, Sadaf; Maroofian, Reza

2018-03-12

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
RNA-Seq-based transcriptome profiling of early nitrogen deficiency response in cucumber seedlings provides new insight into the putative nitrogen regulatory network.

PubMed

Zhao, Wenchao; Yang, Xueyong; Yu, Hongjun; Jiang, Weijie; Sun, Na; Liu, Xiaoran; Liu, Xiaolin; Zhang, Xiaomeng; Wang, Yan; Gu, Xingfang

2015-03-01

Nitrogen (N) is both an important macronutrient and a signal for plant growth and development. However, the early regulatory mechanism of plants in response to N starvation is not well understood, especially in cucumber, an economically important crop that normally consumes excessive N during production. In this study, the early time-course transcriptome response of cucumber leaves under N deficiency was monitored using RNA sequencing (RNA-Seq). More than 23,000 transcripts were examined in cucumber leaves, of which 364 genes were differentially expressed in response to N deficiency. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, gene ontology (GO) and protein-protein interaction analysis, 64 signaling-related N-deficiency-responsive genes were identified. Furthermore, the potential regulatory mechanisms of anthocyanin accumulation, Chl decline and cell wall remodeling were assessed at the transcription level. Increased ascorbic acid synthesis was identified in cucumber seedlings and fruit under N-deficient conditions, and a new corresponding regulatory hypothesis has been proposed. A data cross-comparison between model plants and cucumber was made, and some common and specific N-deficient response mechanisms were found in the present study. Our study provides novel insights into the responses of cucumber to nitrogen starvation at the global transcriptome level, which are expected to be highly useful for dissecting the N response pathways in this major vegetable and for improving N fertilization practices. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency

PubMed Central

2012-01-01

Background Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. Results A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. Conclusions The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency. PMID:22433273
Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta.

PubMed

Nicolay, Nils H; Carter, Rebecca; Hatch, Stephanie B; Schultz, Niklas; Prevo, Remko; McKenna, W Gillies; Helleday, Thomas; Sharma, Ricky A

2012-11-01

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.
Investigation of flange failures in falsework cap and sill beams : recommendations for the design of beams and posts in bridge falsework.

DOT National Transportation Integrated Search

2008-12-01

Recent field observations in bridge falsework identified potential deficiencies in the design of falsework resulting in : localized bending in sill and cap beam flanges and lateral buckling in other beams. Possible limits states associated with : the...
Glucose-6-Phosphate Dehydrogenase Deficiency Genetic Variants in Malaria Patients in Southwestern Ethiopia.

PubMed

Carter, Tamar E; Mekonnen, Seleshi Kebede; Lopez, Karen; Bonnell, Victoria; Damodaran, Lambodhar; Aseffa, Abraham; Janies, Daniel A

2018-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked erythrocyte enzyme disorder with relevance to malaria treatment policy. Treatment with the antimalarial primaquine can result in hemolytic anemia in G6PD-deficient patients. With increased interest in primaquine use, it is important to identify G6PD variants in Ethiopia to inform malaria treatment policy. In the present study, mutations in the G6PD gene are identified in a sample of patients with malaria in Jimma town in southwest Ethiopia. Plasmodium species of infection were confirmed using polymerase chain reaction (PCR) and gel electrophoresis. PCR and Sanger sequencing were performed to observe a portion of the G6PD gene where the common G6PD mutations (A376G, G202A, and C563T) are found. Molecular analysis revealed that most of the samples were single Plasmodium vivax infections (83.7%). For G6PD genotyping, A376G was detected in 23.26% of individuals, whereas G202A and C563T were absent. Three other uncommon mutations were identified: rs782669677 (535G→A), rs370658483, (485 + 37 G→T), and a new mutation at chrX:154535443(C→T). Bioinformatic analysis of these mutations' potential functional impact suggests minimal effect on protein function. The discovery of both common and uncommon G6PD mutations contributes to the discussion on G6PD deficiency and appropriate primaquine treatment in Ethiopia.
MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism.

PubMed

Grolmusz, Vince Kornél; Borka, Katalin; Kövesdi, Annamária; Németh, Kinga; Balogh, Katalin; Dékány, Csaba; Kiss, András; Szentpéteri, Anna; Sármán, Beatrix; Somogyi, Anikó; Csajbók, Éva; Valkusz, Zsuzsanna; Tóth, Miklós; Igaz, Péter; Rácz, Károly; Patócs, Attila

2017-09-01

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.
Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis.

PubMed

Ryu, Moon-Suhn; Langkamp-Henken, Bobbi; Chang, Shou-Mei; Shankar, Meena N; Cousins, Robert J

2011-12-27

Implementation of zinc interventions for subjects suspected of being zinc-deficient is a global need, but is limited due to the absence of reliable biomarkers. To discover molecular signatures of human zinc deficiency, a combination of transcriptome, cytokine, and microRNA analyses was applied to a dietary zinc depletion/repletion protocol with young male human subjects. Concomitant with a decrease in serum zinc concentration, changes in buccal and blood gene transcripts related to zinc homeostasis occurred with zinc depletion. Microarray analyses of whole blood RNA revealed zinc-responsive genes, particularly, those associated with cell cycle regulation and immunity. Responses of potential signature genes of dietary zinc depletion were further assessed by quantitative real-time PCR. The diagnostic properties of specific serum microRNAs for dietary zinc deficiency were identified by acute responses to zinc depletion, which were reversible by subsequent zinc repletion. Depression of immune-stimulated TNFα secretion by blood cells was observed after low zinc consumption and may serve as a functional biomarker. Our findings introduce numerous novel candidate biomarkers for dietary zinc status assessment using a variety of contemporary technologies and which identify changes that occur prior to or with greater sensitivity than the serum zinc concentration which represents the current zinc status assessment marker. In addition, the results of gene network analysis reveal potential clinical outcomes attributable to suboptimal zinc intake including immune function defects and predisposition to cancer. These demonstrate through a controlled depletion/repletion dietary protocol that the illusive zinc biomarker(s) can be identified and applied to assessment and intervention strategies.
Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency.

PubMed

Giacopuzzi, Edoardo; Laffranchi, Mattia; Berardelli, Romina; Ravasio, Viola; Ferrarotti, Ilaria; Gooptu, Bibek; Borsani, Giuseppe; Fra, Annamaria

2018-06-07

The growth of publicly available data informing upon genetic variations, mechanisms of disease and disease sub-phenotypes offers great potential for personalised medicine. Computational approaches are likely required to assess large numbers of novel genetic variants. However, the integration of genetic, structural and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin. We compiled a comprehensive database of SERPINA1 coding mutations and assigned them apparent pathological relevance based upon available data. 'Benign' and 'Pathogenic' mutations were used to assess performance of 31 pathogenicity predictors. Well-performing algorithms clustered the subset of variants known to be severely pathogenic with high scores. Eight new mutations identified in the ExAC database and achieving high scores were selected for characterisation in cell models and showed secretory deficiency and polymer formation, supporting the predictive power of our computational approach. The behaviour of the pathogenic new variants and consistent outliers were rationalised by considering the protein structural context and residue conservation. These findings highlight the potential of computational methods to provide meaningful predictions of the pathogenic significance of novel mutations and identify areas for further investigation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
The chlorophyll-deficient golden leaf mutation in cucumber is due to a single nucleotide substitution in CsChlI for magnesium chelatase I subunit.

PubMed

Gao, Meiling; Hu, Liangliang; Li, Yuhong; Weng, Yiqun

2016-10-01

The cucumber chlorophyll-deficient golden leaf mutation is due to a single nucleotide substitution in the CsChlI gene for magnesium chelatase I subunit which plays important roles in the chlorophyll biosynthesis pathway. The Mg-chelatase catalyzes the insertion of Mg(2+) into the protoporphyrin IX in the chlorophyll biosynthesis pathway, which is a protein complex encompassing three subunits CHLI, CHLD, and CHLH. Chlorophyll-deficient mutations in genes encoding the three subunits have played important roles in understanding the structure, function and regulation of this important enzyme. In an EMS mutagenesis population, we identified a chlorophyll-deficient mutant C528 with golden leaf color throughout its development which was viable and able to set fruits and seeds. Segregation analysis in multiple populations indicated that this leaf color mutation was recessively inherited and the green color showed complete dominance over golden color. Map-based cloning identified CsChlI as the candidate gene for this mutation which encoded the CHLI subunit of cucumber Mg-chelatase. The 1757-bp CsChlI gene had three exons and a single nucleotide change (G to A) in its third exon resulted in an amino acid substitution (G269R) and the golden leaf color in C528. This mutation occurred in the highly conserved nucleotide-binding domain of the CHLI protein in which chlorophyll-deficient mutations have been frequently identified. The mutant phenotype, CsChlI expression pattern and the mutated residue in the CHLI protein suggested the mutant allele in C528 is unique among mutations identified so far in different species. This golden leaf mutant not only has its potential in cucumber breeding, but also provides a useful tool in understanding the CHLI function and its regulation in the chlorophyll biosynthesis pathway as well as chloroplast development.
Circadian clock-deficient mice as a tool for exploring disease etiology.

PubMed

Doi, Masao

2012-01-01

One of the most significant conceptual changes brought about by the analysis of circadian clock-deficient mice is that abnormalities in the circadian clock are linked not only to sleep arousal disorder but also to a wide variety of common diseases, including hypertension, diabetes, obesity, and cancer. It has recently been shown that the disruption of the two cryptochrome genes Cry1 and Cry2-core elements of the circadian clock-induces salt-dependent hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. This adrenal disorder occurs as a result of increased expression of Hsd3b6, a newly identified steroidogenic enzyme that regulates aldosterone production within the adrenal zona glomerular cells. Importantly, this enzyme is functionally conserved in humans, and the pathophysiologic condition of human idiopathic hyperaldosteronism resembles that of Cry1/2-deficient mice. This review highlights the potential utility of circadian clock-deficient mice as a tool for exploring hitherto unknown disease etiology linked to the circadian clock.
Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes.

PubMed

Tran, Thai Q; Ishak Gabra, Mari B; Lowman, Xazmin H; Yang, Ying; Reid, Michael A; Pan, Min; O'Connor, Timothy R; Kong, Mei

2017-11-01

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.
Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes

PubMed Central

Tran, Thai Q.; Ishak Gabra, Mari B.; Lowman, Xazmin H.; Yang, Ying; Reid, Michael A.; Pan, Min; O’Connor, Timothy R.

2017-01-01

Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer. PMID:29107960
Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation

PubMed Central

Kang, Myung-Su; Lee, Dohyun; Lee, Seung-Hyun

2017-01-01

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor–mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD. PMID:28899869

Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation.

PubMed

Kang, Myung-Su; Choi, Tae-Yong; Ryu, Hye Guk; Lee, Dohyun; Lee, Seung-Hyun; Choi, Se-Young; Kim, Kyong-Tai

2017-10-02

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3 -deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3 -deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3 -deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD. © 2017 Kang et al.
Serum Hepcidin Concentrations Decline during Pregnancy and May Identify Iron Deficiency: Analysis of a Longitudinal Pregnancy Cohort in The Gambia.

PubMed

Bah, Amat; Pasricha, Sant-Rayn; Jallow, Momodou W; Sise, Ebrima A; Wegmuller, Rita; Armitage, Andrew E; Drakesmith, Hal; Moore, Sophie E; Prentice, Andrew M

2017-06-01

Background: Antenatal anemia is a risk factor for adverse maternal and fetal outcomes and is prevalent in sub-Saharan Africa. Less than half of antenatal anemia is considered responsive to iron; identifying women in need of iron may help target interventions. Iron absorption is governed by the iron-regulatory hormone hepcidin. Objective: We sought to characterize changes in hepcidin and its associations with indexes of iron stores, erythropoiesis, and inflammation at weeks 14, 20, and 30 of gestation and to assess hepcidin's diagnostic potential as an index of iron deficiency. Methods: We measured hemoglobin and serum hepcidin, ferritin, soluble transferrin receptor (sTfR), and C-reactive protein (CRP) at 14, 20, and 30 wk of gestation in a cohort of 395 Gambian women recruited to a randomized controlled trial. Associations with hepcidin were measured by using linear regression, and hepcidin's diagnostic test accuracy [area under the receiver operating characteristic curve (AUC ROC ), sensitivity, specificity, cutoffs] for iron deficiency at each time point was analyzed. Results: The prevalence of anemia increased from 34.6% at 14 wk of gestation to 50.0% at 20 wk. Hepcidin concentrations declined between study enrollment and 20 wk, whereas ferritin declined between 20 and 30 wk of gestation. The variations in hepcidin explained by ferritin, sTfR, and CRP declined over pregnancy. The AUC ROC values for hepcidin to detect iron deficiency (defined as ferritin <15 μg/L) were 0.86, 0.83, and 0.84 at 14, 20, and 30 wk, respectively. Hepcidin was superior to hemoglobin and sTfR as an indicator of iron deficiency. Conclusions: In Gambian pregnant women, hepcidin appears to be a useful diagnostic test for iron deficiency and may enable the identification of cases for whom iron would be beneficial. Hepcidin suppression in the second trimester suggests a window for optimal timing for antenatal iron interventions. Hemoglobin does not effectively identify iron deficiency in pregnancy. This trial was registered at www.isrctn.com as ISRCTN49285450.
40 CFR 141.723 - Requirements to respond to significant deficiencies identified in sanitary surveys performed by EPA.

Code of Federal Regulations, 2011 CFR

2011-07-01

... deficiencies identified in sanitary surveys performed by EPA. 141.723 Section 141.723 Protection of Environment... REGULATIONS Enhanced Treatment for Cryptosporidium Requirements for Sanitary Surveys Performed by Epa § 141.723 Requirements to respond to significant deficiencies identified in sanitary surveys performed by...
40 CFR 141.723 - Requirements to respond to significant deficiencies identified in sanitary surveys performed by EPA.

Code of Federal Regulations, 2014 CFR

2014-07-01

... deficiencies identified in sanitary surveys performed by EPA. 141.723 Section 141.723 Protection of Environment... REGULATIONS Enhanced Treatment for Cryptosporidium Requirements for Sanitary Surveys Performed by Epa § 141.723 Requirements to respond to significant deficiencies identified in sanitary surveys performed by...
40 CFR 141.723 - Requirements to respond to significant deficiencies identified in sanitary surveys performed by EPA.

Code of Federal Regulations, 2013 CFR

2013-07-01

... deficiencies identified in sanitary surveys performed by EPA. 141.723 Section 141.723 Protection of Environment... REGULATIONS Enhanced Treatment for Cryptosporidium Requirements for Sanitary Surveys Performed by Epa § 141.723 Requirements to respond to significant deficiencies identified in sanitary surveys performed by...
40 CFR 141.723 - Requirements to respond to significant deficiencies identified in sanitary surveys performed by EPA.

Code of Federal Regulations, 2012 CFR

2012-07-01

... deficiencies identified in sanitary surveys performed by EPA. 141.723 Section 141.723 Protection of Environment... REGULATIONS Enhanced Treatment for Cryptosporidium Requirements for Sanitary Surveys Performed by Epa § 141.723 Requirements to respond to significant deficiencies identified in sanitary surveys performed by...
40 CFR 141.723 - Requirements to respond to significant deficiencies identified in sanitary surveys performed by EPA.

Code of Federal Regulations, 2010 CFR

2010-07-01

... deficiencies identified in sanitary surveys performed by EPA. 141.723 Section 141.723 Protection of Environment... REGULATIONS Enhanced Treatment for Cryptosporidium Requirements for Sanitary Surveys Performed by Epa § 141.723 Requirements to respond to significant deficiencies identified in sanitary surveys performed by...
Identification of genotoxic compounds using isogenic DNA repair deficient DT40 cell lines on a quantitative high throughput screening platform

PubMed Central

Nishihara, Kana; Huang, Ruili; Zhao, Jinghua; Shahane, Sampada A.; Witt, Kristine L.; Smith-Roe, Stephanie L.; Tice, Raymond R.; Takeda, Shunichi; Xia, Menghang

2016-01-01

DNA repair pathways play a critical role in maintaining cellular homeostasis by repairing DNA damage induced by endogenous processes and xenobiotics, including environmental chemicals. Induction of DNA damage may lead to genomic instability, disruption of cellular homeostasis and potentially tumours. Isogenic chicken DT40 B-lymphocyte cell lines deficient in DNA repair pathways can be used to identify genotoxic compounds and aid in characterising the nature of the induced DNA damage. As part of the US Tox21 program, we previously optimised several different DT40 isogenic clones on a high-throughput screening platform and confirmed the utility of this approach for detecting genotoxicants by measuring differential cytotoxicity in wild-type and DNA repair-deficient clones following chemical exposure. In the study reported here, we screened the Tox21 10K compound library against two isogenic DNA repair-deficient DT40 cell lines (KU70 −/−/RAD54 −/− and REV3 −/−) and the wild-type cell line using a cell viability assay that measures intracellular adenosine triphosphate levels. KU70 and RAD54 are genes associated with DNA double-strand break repair processes, and REV3 is associated with translesion DNA synthesis pathways. Active compounds identified in the primary screening included many well-known genotoxicants (e.g. adriamycin, melphalan) and several compounds previously untested for genotoxicity. A subset of compounds was further evaluated by assessing their ability to induce micronuclei and phosphorylated H2AX. Using this comprehensive approach, three compounds with previously undefined genotoxicity—2-oxiranemethanamine, AD-67 and tetraphenylolethane glycidyl ether—were identified as genotoxic. These results demonstrate the utility of this approach for identifying and prioritising compounds that may damage DNA. PMID:26243743
Genome-Wide Identification of Medicago Peptides Involved in Macronutrient Responses and Nodulation1[OPEN

PubMed Central

Dai, Xinbin; Zhuang, Zhaohong; Torres-Jerez, Ivone; Nogales, Joaquina

2017-01-01

Growing evidence indicates that small, secreted peptides (SSPs) play critical roles in legume growth and development, yet the annotation of SSP-coding genes is far from complete. Systematic reannotation of the Medicago truncatula genome identified 1,970 homologs of established SSP gene families and an additional 2,455 genes that are potentially novel SSPs, previously unreported in the literature. The expression patterns of known and putative SSP genes based on 144 RNA sequencing data sets covering various stages of macronutrient deficiencies and symbiotic interactions with rhizobia and mycorrhiza were investigated. Focusing on those known or suspected to act via receptor-mediated signaling, 240 nutrient-responsive and 365 nodulation-responsive Signaling-SSPs were identified, greatly expanding the number of SSP gene families potentially involved in acclimation to nutrient deficiencies and nodulation. Synthetic peptide applications were shown to alter root growth and nodulation phenotypes, revealing additional regulators of legume nutrient acquisition. Our results constitute a powerful resource enabling further investigations of specific SSP functions via peptide treatment and reverse genetics. PMID:29030416
[A neonate with anaemia of prematurity: zinc protoporphyrin identifies iron deficiency anaemia without iron deficiency].

PubMed

van der Feen, Diederik E; van Hillegersberg, Jacqueline L A M; Schippers, Johannes A

2015-01-01

Anaemia is a common problem in premature infants and is generally easy to treat with iron supplementation. If the anaemia persists despite appropriate correction of deficiencies, more extensive evaluation is required. We describe a case of a premature male infant with a production-deficient anaemia without metabolic deficiencies, eventually identified as anaemia of prematurity. This type of anaemia is commonly diagnosed but its highly variable and complex aetiology and phenotype are often poorly understood. A probable explanation for the anaemia of prematurity in this case was a transient iron incorporation defect, identifiable by high levels of zinc protoporphyrin.
Clinical, physiological and pathological characterisation of the sensory predominant peripheral neuropathy in copper deficiency.

PubMed

Taylor, Sean W; Laughlin, Ruple S; Kumar, Neeraj; Goodman, Brent; Klein, Christopher J; Dyck, Peter J; Dyck, P James B

2017-10-01

Myelopathy is considered the most common neurological complication of copper deficiency. Concurrent peripheral neuropathy has been recognised in association with copper deficiency but has not been well characterised. To characterise the clinical, physiological and pathological features of copper-deficient peripheral neuropathy. Patients with simultaneous copper deficiency (<0.78 μg/mL) and peripheral neuropathy seen at the Mayo Clinic from 1985 to 2005 were identified. 34 patients were identified (median age 55 years, range 36-78) including 24 women and 10 men. Myelopathy was found in 21 patients. Median serum copper level was 0.11 μg/mL (range 0-0.58). The most frequent clinical and electrophysiological pattern of neuropathy was a sensory predominant length-dependent peripheral neuropathy (71%). Somatosensory evoked potentials demonstrated central slowing supporting myelopathy (96%). Quantitative sensory testing demonstrated both small and large fibre involvement (100%). Autonomic reflex screens (77%) and thermoregulatory sweat test (67%) confirmed sudomotor dysfunction. 14 cutaneous nerve biopsies revealed loss of myelinated nerve fibres (86%), increased regenerative clusters (50%), increased rates of axonal degeneration (91%) and increased numbers of empty nerve strands (73%). 71% of biopsies demonstrated epineurial perivascular inflammation. An axonal, length-dependent sensory predominant peripheral neuropathy causing sensory ataxia is characteristic of copper deficiency usually co-occurring with myelopathy. Neurophysiological testing confirms involvement of large, greater than small fibres. The pathological findings suggest axonal degeneration and repair. Inflammatory infiltrates are common but are small and of doubtful pathological significance. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Dietary phytate, zinc and hidden zinc deficiency.

PubMed

Sandstead, Harold H; Freeland-Graves, Jeanne H

2014-10-01

Epidemiological data suggest at least one in five humans are at risk of zinc deficiency. This is in large part because the phytate in cereals and legumes has not been removed during food preparation. Phytate, a potent indigestible ligand for zinc prevents it's absorption. Without knowledge of the frequency of consumption of foods rich in phytate, and foods rich in bioavailable zinc, the recognition of zinc deficiency early in the illness may be difficult. Plasma zinc is insensitive to early zinc deficiency. Serum ferritin concentration≤20μg/L is a potential indirect biomarker. Early effects of zinc deficiency are chemical, functional and may be "hidden". The clinical problem is illustrated by 2 studies that involved US Mexican-American children, and US premenopausal women. The children were consuming home diets that included traditional foods high in phytate. The premenopausal women were not eating red meat on a regular basis, and their consumption of phytate was mainly from bran breakfast cereals. In both studies the presence of zinc deficiency was proven by functional responses to controlled zinc treatment. In the children lean-mass, reasoning, and immunity were significantly affected. In the women memory, reasoning, and eye-hand coordination were significantly affected. A screening self-administered food frequency questionnaire for office might help caregiver's identify patients at risk of zinc deficiency. Copyright © 2014 Elsevier GmbH. All rights reserved.
Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta

PubMed Central

Sharma, Ricky A.

2012-01-01

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt’s lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control. PMID:22822095
Prevalence and Factors Associated with Vitamin D Deficiency and Hyperparathyroidism in HIV-Infected Patients Treated in Barcelona.

PubMed

Lerma, Elisabet; Molas, M Ema; Montero, M Milagro; Guelar, Ana; González, Alicia; Villar, Judith; Diez, Adolf; Knobel, Hernando

2012-01-01

Vitamin D deficiency is an important problem in patients with chronic conditions including those with human immunodeficiency virus (HIV) infection. The aim of this cross-sectional study was to identify the prevalence and factors associated with vitamin D deficiency and hyperparathyroidism in HIV patients attended in Barcelona. Cholecalciferol (25OH vitamin D3) and PTH levels were measured. Vitamin D insufficiency was defined as 25(OH) D < 20 ng/mL and deficiency as <12 ng/mL. Hyperparathyroidism was defined as PTH levels >65 pg/mL. Cases with chronic kidney failure, liver disease, treatments or conditions potentially affecting bone metabolism were excluded. Among the 566 patients included, 56.4% were exposed to tenofovir. Vitamin D insufficiency was found in 71.2% and 39.6% of those had deficiency. PTH was measured in 228 subjects, and 86 of them (37.7%) showed high levels. Adjusted predictors of vitamin D deficiency were nonwhite race and psychiatric comorbidity, while lipoatrophy was a protective factor. Independent risk factors of hyperparathyroidism were vitamin D < 12 ng/mL (OR: 2.14, CI 95%: 1.19-3.82, P: 0.01) and tenofovir exposure (OR: 3.55, CI 95%: 1.62-7.7, P: 0.002). High prevalence of vitamin deficiency and hyperparathyroidism was found in an area with high annual solar exposure.
Prevalence and Factors Associated with Vitamin D Deficiency and Hyperparathyroidism in HIV-Infected Patients Treated in Barcelona

PubMed Central

Lerma, Elisabet; Molas, M. Ema; Montero, M. Milagro; Guelar, Ana; González, Alicia; Villar, Judith; Diez, Adolf; Knobel, Hernando

2012-01-01

Vitamin D deficiency is an important problem in patients with chronic conditions including those with human immunodeficiency virus (HIV) infection. The aim of this cross-sectional study was to identify the prevalence and factors associated with vitamin D deficiency and hyperparathyroidism in HIV patients attended in Barcelona. Cholecalciferol (25OH vitamin D3) and PTH levels were measured. Vitamin D insufficiency was defined as 25(OH) D < 20 ng/mL and deficiency as <12 ng/mL. Hyperparathyroidism was defined as PTH levels >65 pg/mL. Cases with chronic kidney failure, liver disease, treatments or conditions potentially affecting bone metabolism were excluded. Among the 566 patients included, 56.4% were exposed to tenofovir. Vitamin D insufficiency was found in 71.2% and 39.6% of those had deficiency. PTH was measured in 228 subjects, and 86 of them (37.7%) showed high levels. Adjusted predictors of vitamin D deficiency were nonwhite race and psychiatric comorbidity, while lipoatrophy was a protective factor. Independent risk factors of hyperparathyroidism were vitamin D < 12 ng/mL (OR: 2.14, CI 95%: 1.19–3.82, P: 0.01) and tenofovir exposure (OR: 3.55, CI 95%: 1.62–7.7, P: 0.002). High prevalence of vitamin deficiency and hyperparathyroidism was found in an area with high annual solar exposure. PMID:24052874
Determination of optimal cutoff value to accurately identify glucose-6-phosphate dehydrogenase-deficient heterozygous female neonates.

PubMed

Miao, Jing-Kun; Chen, Qi-Xiong; Bao, Li-Ming; Huang, Yi; Zhang, Juan; Wan, Ke-Xing; Yi, Jing; Wang, Shi-Yi; Zou, Lin; Li, Ting-Yu

2013-09-23

Conventional screening tests to assess G6PD deficiency use a low cutoff value of 2.10 U/gHb which may not be adequate for detecting females with heterozygous deficiency. The aim of present study was to determine an appropriate cutoff value with increased sensitivity in identifying G6PD-deficient heterozygous females. G6PD activity analysis was performed on 51,747 neonates using semi-quantitative fluorescent spot test. Neonates suspected with G6PD deficiency were further analyzed using quantitatively enzymatic assay and for common G6PD mutations. The cutoff values of G6PD activity were estimated using the receiver operating characteristic curve. Our results demonstrated that using 2.10 U/g Hb as a cutoff, the sensitivity of the assay to detect female neonates with G6PD heterozygous deficiency was 83.3%, as compared with 97.6% using 2.55 U/g Hb as a cutoff. The high cutoff identified 21% (8/38) of the female neonates with partial G6PD deficiency which were not detected with 2.10 U/g Hb. Our study found that high cutoffs, 2.35 and 2.55 U/g Hb, would increase assay's sensitivity to identify male and female G6PD deficiency neonates, respectively. We established a reliable cutoff value of G6PD activity with increased sensitivity in identifying female newborns with partial G6PD deficiency. Copyright © 2013 Elsevier B.V. All rights reserved.
Vitamin B12 deficiency is associated with geographical latitude and solar radiation in the older population.

PubMed

Cabrera, Sebastián; Benavente, David; Alvo, Miriam; de Pablo, Paola; Ferro, Charles J

2014-11-01

Vitamin B12 and folic acid deficiency are common in the older and are associated with several conditions including anaemia, cardiovascular disease, cognitive impairment and cancer. Evidence from in vitro studies suggests that solar radiation can degrade both vitamins in the skin. Chile is the longest country in the world running perfectly North-South making it an ideal place to study potential associations of latitude and solar radiation on vitamin B12 and folic acid deficiency. The objective was to examine the association between vitamin B12 and folic acid deficiencies and latitude. Plasma samples were collected from Chileans aged 65+ years (n=1013) living across the whole country and assayed for vitamin B12 and folic acid concentrations as part of the Chilean Health Survey 2009-2010, which is a national representative sample study. Overall, the prevalence of vitamin B12 deficiency was 11.3%, with the prevalence in the North of the country being significantly greater than in the Central and South zones (19.1%,10.5%, and 5.7%, respectively; P<0.001). The prevalence of folic acid deficiency in the whole cohort was 0.7% with no difference between the 3 geographical zones. Using logistic regression analyses, vitamin B12 deficiency was significantly associated with geographical latitude (OR 0.910 [95% confidence intervals 0.890-0.940], P<0.001) and solar radiation (OR 1.203 [95% confidence intervals 1.119-1.294], P<0.001). These associations persisted after adjustments for confounders (OR 0.930, P<0.001 and 1.198, P=0.002, respectively). In the Chilean population of 65+, the prevalence of vitamin B12 deficiency is associated with living closer to the Equator and solar radiation. Although degradation by solar radiation might explain this observation, further work is required to establish the potential mechanisms. In countries that routinely fortify food with folic acid, efforts to identify vitamin B12 deficiency might be more cost-efficiently targeted in areas closest to the Equator. Copyright © 2014 Elsevier B.V. All rights reserved.
Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: A BabySeq Project case report.

PubMed

Murry, Jaclyn B; Machini, Kalotina; Ceyhan-Birsoy, Ozge; Kritzer, Amy; Krier, Joel B; Lebo, Matthew S; Fayer, Shawn; Genetti, Casie A; Vannoy, Grace E; Yu, Timothy W; Agrawal, Pankaj B; Parad, Richard B; Holm, Ingrid A; McGuire, Amy L; Green, Robert C; Beggs, Alan H; Rehm, Heidi L; Project, The BabySeq

2018-05-04

Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cut-off into the normal range. To determine whether the infant was biotinidase deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BTD, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial biotinidase deficiency, and informed this novel splice site's reclassification emphasizing the importance of combining iterative genetic and phenotypic evaluations. Cold Spring Harbor Laboratory Press.
MCPIP1 Deficiency in Mice Results in Severe Anemia Related to Autoimmune Mechanisms

PubMed Central

Zhou, Zhou; Miao, Ruidong; Huang, Shengping; Elder, Brandon; Quinn, Tim; Papasian, Christopher J.; Zhang, Jifeng; Fan, Daping; Chen, Y. Eugene; Fu, Mingui

2013-01-01

Autoimmune gastritis is an organ-specific autoimmune disease of the stomach associated with pernicious anemia. The previous work from us and other groups identified MCPIP1 as an essential factor controlling inflammation and immune homeostasis. MCPIP1-/- developed severe anemia. However, the mechanisms underlying this phenotype remain unclear. In the present study, we found that MCPIP1 deficiency in mice resulted in severe anemia related to autoimmune mechanisms. Although MCPIP1 deficiency did not affect erythropoiesis per se, the erythropoiesis in MCPIP1-/- bone marrow erythroblasts was significantly attenuated due to iron and vitamin B12 (VB12) deficiency, which was mainly resulted from autoimmunity-associated gastritis and parietal cell loss. Consistently, exogenous supplement of iron and VB12 greatly improved the anemia phenotype of MCPIP1-/- mice. Finally, we have evidence suggesting that autoimmune hemolysis may also contribute to anemia phenotype of MCPIP1-/- mice. Taken together, our study suggests that MCPIP1 deficiency in mice leads to the development of autoimmune gastritis and pernicious anemia. Thus, MCPIP1-/- mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease. PMID:24324805
Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS.

PubMed

Ma, Bo; Li, Xiaotian; Zhang, Qi; Wu, Di; Wang, Guangji; A, Jiye; Sun, Jianguo; Li, Jing; Liu, Yinhui; Wang, Yonglu; Ying, Hanjie

2013-10-15

A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110 mg/kg/day for the prevention and 220 mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss. © 2013 Elsevier B.V. All rights reserved.

Spatial multi-scale variability of soil nutrients in relation to environmental factors in a typical agricultural region, eastern China.

PubMed

Liu, Yang; Lv, Jianshu; Zhang, Bing; Bi, Jun

2013-04-15

Identifying the sources of spatial variability and deficiency risk of soil nutrients is a crucial issue for soil and agriculture management. A total of 1247 topsoil samples (0-20 cm) were collected at the nodes of a 2×2 km grid in Rizhao City and the contents of soil organic carbon (OC), total nitrogen (TN), and total phosphorus (TP) were determined. Factorial kriging analysis (FKA), stepwise multiple regression, and indicator kriging (IK) were appled to investigate the scale dependent correlations among soil nutrients, identify the sources of spatial variability at each spatial scale, and delineate the potential risk of soil nutrient deficiency. Linear model of co-regionalization (LMC) fitting indicated that the presence of multi-scale variation was comprised of nugget effect, an exponential structure with a range of 12 km (local scale), and a spherical structure with a range of 84 km (regional scale). The short-range variation of OC and TN was mainly dominated by land use types, and TP was controlled by terrain. At long-range scale, spatial variation of OC, TN, and TP was dominated by parent material. Indicator kriging maps depicted the probability of soil nutrient deficiency compared with the background values in eastern Shandong province. The high deficiency risk area of all nutrient integration was mainly located in eastern and northwestern parts. Copyright © 2013 Elsevier B.V. All rights reserved.
Strategies to avoid the loss of developmental potential in more than 200 million children in the developing world.

PubMed

Engle, Patrice L; Black, Maureen M; Behrman, Jere R; Cabral de Mello, Meena; Gertler, Paul J; Kapiriri, Lydia; Martorell, Reynaldo; Young, Mary Eming

2007-01-20

This paper is the third in the Child Development Series. The first paper showed that more than 200 million children under 5 years of age in developing countries do not reach their developmental potential. The second paper identified four well-documented risks: stunting, iodine deficiency, iron deficiency anaemia, and inadequate cognitive stimulation, plus four potential risks based on epidemiological evidence: maternal depression, violence exposure, environmental contamination, and malaria. This paper assesses strategies to promote child development and to prevent or ameliorate the loss of developmental potential. The most effective early child development programmes provide direct learning experiences to children and families, are targeted toward younger and disadvantaged children, are of longer duration, high quality, and high intensity, and are integrated with family support, health, nutrition, or educational systems and services. Despite convincing evidence, programme coverage is low. To achieve the Millennium Development Goals of reducing poverty and ensuring primary school completion for both girls and boys, governments and civil society should consider expanding high quality, cost-effective early child development programmes.
Obtaining Valid Safety Data for Software Safety Measurement and Process Improvement

NASA Technical Reports Server (NTRS)

Basili, Victor r.; Zelkowitz, Marvin V.; Layman, Lucas; Dangle, Kathleen; Diep, Madeline

2010-01-01

We report on a preliminary case study to examine software safety risk in the early design phase of the NASA Constellation spaceflight program. Our goal is to provide NASA quality assurance managers with information regarding the ongoing state of software safety across the program. We examined 154 hazard reports created during the preliminary design phase of three major flight hardware systems within the Constellation program. Our purpose was two-fold: 1) to quantify the relative importance of software with respect to system safety; and 2) to identify potential risks due to incorrect application of the safety process, deficiencies in the safety process, or the lack of a defined process. One early outcome of this work was to show that there are structural deficiencies in collecting valid safety data that make software safety different from hardware safety. In our conclusions we present some of these deficiencies.
LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin

PubMed Central

Shackelford, David B.; Abt, Evan; Gerken, Laurie; Vasquez, Debbie S.; Seki, Atsuko; Leblanc, Mathias; Wei, Liu; Fishbein, Michael C.; Czernin, Johannes; Mischel, Paul S.; Shaw, Reuben J.

2013-01-01

SUMMARY The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ~20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors. PMID:23352126
LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.

PubMed

Shackelford, David B; Abt, Evan; Gerken, Laurie; Vasquez, Debbie S; Seki, Atsuko; Leblanc, Mathias; Wei, Liu; Fishbein, Michael C; Czernin, Johannes; Mischel, Paul S; Shaw, Reuben J

2013-02-11

The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors. Copyright © 2013 Elsevier Inc. All rights reserved.
Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin

PubMed Central

Zheng, Chunlei; Zhu, Min; Tao, Jiayi; Vasievich, Matthew P.; Baines, Andrea; Kim, Jinoh; Schekman, Randy; Kaufman, Randal J.; Ginsburg, David

2011-01-01

The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1−/− mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and α1-antitrypsin as additional potential cargoes for LMAN1, no differences were observed between wild-type and Lman1−/− mice in the levels of cathepsin C and cathepsin Z in liver lysates or α1-antitrypsin levels in plasma. LMAN1 deficiency had no apparent effect on COPII-coated vesicle formation in an in vitro assay. However, the ER in Lman1−/− hepatocytes is slightly distended, with significant accumulation of α1-antitrypsin and GRP78. An unexpected, partially penetrant, perinatal lethality was observed for Lman1−/− mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins. PMID:21795745
Novel genetic capacitors and potentiators for the natural genetic variation of sensory bristles and their trait specificity in Drosophila melanogaster.

PubMed

Takahashi, Kazuo H

2015-11-01

Cryptic genetic variation (CGV) is defined as the genetic variation that has little effect on phenotypic variation under a normal condition, but contributes to heritable variation under environmental or genetic perturbations. Genetic buffering systems that suppress the expression of CGV and store it in a population are called genetic capacitors, and the opposite systems are called genetic potentiators. One of the best-known candidates for a genetic capacitor and potentiator is the molecular chaperone protein, HSP90, and one of its characteristics is that it affects the genetic variation in various morphological traits. However, it remains unclear whether the wide-ranging effects of HSP90 on a broad range of traits are a general feature of genetic capacitors and potentiators. In the current study, I searched for novel genetic capacitors and potentiators for quantitative bristle traits of Drosophila melanogaster and then investigated the trait specificity of their genetic buffering effect. Three bristle traits of D. melanogaster were used as the target traits, and the genomic regions with genetic buffering effects were screened using the 61 genomic deficiencies examined previously for genetic buffering effects in wing shape. As a result, four and six deficiencies with significant effects on increasing and decreasing the broad-sense heritability of the bristle traits were identified, respectively. Of the 18 deficiencies with significant effects detected in the current study and/or by the previous study, 14 showed trait-specific effects, and four affected the genetic buffering of both bristle traits and wing shape. This suggests that most genetic capacitors and potentiators exert trait-specific effects, but that general capacitors and potentiators with effects on multiple traits also exist. © 2015 John Wiley & Sons Ltd.
Effect of sulphur deprivation on osmotic potential components and nitrogen metabolism in oilseed rape leaves: identification of a new early indicator.

PubMed

Sorin, Elise; Etienne, Philippe; Maillard, Anne; Zamarreño, Angel-Mari; Garcia-Mina, José-Maria; Arkoun, Mustapha; Jamois, Frank; Cruz, Florence; Yvin, Jean-Claude; Ourry, Alain

2015-10-01

Identification of early sulphur (S) deficiency indicators is important for species such as Brassica napus, an S-demanding crop in which yield and the nutritional quality of seeds are negatively affected by S deficiency. Because S is mostly stored as SO4 (2-) in leaf cell vacuoles and can be mobilized during S deficiency, this study investigated the impact of S deprivation on leaf osmotic potential in order to identify compensation processes. Plants were exposed for 28 days to S or to chlorine deprivation in order to differentiate osmotic and metabolic responses. While chlorine deprivation had no significant effects on growth, osmotic potential and nitrogen metabolism, Brassica napus revealed two response periods to S deprivation. The first one occurred during the first 13 days during which plant growth was maintained as a result of vacuolar SO4 (2-) mobilization. In the meantime, leaf osmotic potential of S-deprived plants remained similar to control plants despite a reduction in the SO4 (2-) osmotic contribution, which was fully compensated by an increase in NO3 (-), PO4 (3-) and Cl(-) accumulation. The second response occurred after 13 days of S deprivation with a significant reduction in growth, leaf osmotic potential, NO3 (-) uptake and NO3 (-) reductase activity, whereas amino acids and NO3 (-) were accumulated. This kinetic analysis of S deprivation suggested that a ([Cl(-)]+[NO3 (-)]+[PO4 (3-)]):[SO4 (2-)] ratio could provide a relevant indicator of S deficiency, modified nearly as early as the over-expression of genes encoding SO4 (2-) tonoplastic or plasmalemmal transporters, with the added advantage that it can be easily quantified under field conditions. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Vitamin B12–dependent taurine synthesis regulates growth and bone mass

PubMed Central

Roman-Garcia, Pablo; Quiros-Gonzalez, Isabel; Mottram, Lynda; Lieben, Liesbet; Sharan, Kunal; Wangwiwatsin, Arporn; Tubio, Jose; Lewis, Kirsty; Wilkinson, Debbie; Santhanam, Balaji; Sarper, Nazan; Clare, Simon; Vassiliou, George S.; Velagapudi, Vidya R.; Dougan, Gordon; Yadav, Vijay K.

2014-01-01

Both maternal and offspring-derived factors contribute to lifelong growth and bone mass accrual, although the specific role of maternal deficiencies in the growth and bone mass of offspring is poorly understood. In the present study, we have shown that vitamin B12 (B12) deficiency in a murine genetic model results in severe postweaning growth retardation and osteoporosis, and the severity and time of onset of this phenotype in the offspring depends on the maternal genotype. Using integrated physiological and metabolomic analysis, we determined that B12 deficiency in the offspring decreases liver taurine production and associates with abrogation of a growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. Taurine increased GH-dependent IGF1 synthesis in the liver, which subsequently enhanced osteoblast function, and in B12-deficient offspring, oral administration of taurine rescued their growth retardation and osteoporosis phenotypes. These results identify B12 as an essential vitamin that positively regulates postweaning growth and bone formation through taurine synthesis and suggests potential therapies to increase bone mass. PMID:24911144
Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency

PubMed Central

Oyama, Mark A.; Reiken, Steve; Lehnart, Stephan E.; Chittur, Sridar V.; Meurs, Kathryn M.; Stern, Joshua; Marks, Andrew R.

2010-01-01

Objective To examine the presence and effect of calstabin2-deficiency in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC). Animals Thirteen Boxer dogs with ARVC. Materials and methods Tissue samples were collected for histopathology, oligonucleotide microarray, PCR, immunoelectrophoresis, ryanodine channel immunoprecipitation and single-channel recordings, and calstabin2 DNA sequencing. Results In cardiomyopathic Boxer dogs, myocardial calstabin2 mRNA and protein were significantly decreased as compared to healthy control dogs (calstabin2 protein normalized to tetrameric cardiac ryanodine receptor (RyR2) complex: affected, 0.51 ± 0.04; control, 3.81 ± 0.22; P < 0.0001). Calstabin2 deficiency in diseased dog hearts was associated with a significantly increased open probability of single RyR2 channels indicating intracellular Ca2+ leak. PCR-based sequencing of the promoter, exonic and splice site regions of the canine calstabin2 gene did not identify any causative mutations. Conclusions Calstabin2 deficiency is a potential mechanism of Ca2+ leak-induced ventricular arrhythmias and heart disease in Boxer dogs with ARVC. PMID:18515204
Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity

PubMed Central

Casson, Cierra N.; Lefkovith, Ariel J.

2017-01-01

Bacterial pathogens that compromise phagosomal membranes stimulate inflammasome assembly in the cytosol, but the molecular mechanisms by which membrane dynamics regulate inflammasome activity are poorly characterized. We show that in murine dendritic cells (DCs), the endosomal adaptor protein AP-3 –which optimizes toll-like receptor signaling from phagosomes–sustains inflammasome activation by particulate stimuli. AP-3 independently regulates inflammasome positioning and autophagy induction, together resulting in delayed inflammasome inactivation by autophagy in response to Salmonella Typhimurium (STm) and other particulate stimuli specifically in DCs. AP-3-deficient DCs, but not macrophages, hyposecrete IL-1β and IL-18 in response to particulate stimuli in vitro, but caspase-1 and IL-1β levels are restored by silencing autophagy. Concomitantly, AP-3-deficient mice exhibit higher mortality and produce less IL-1β, IL-18, and IL-17 than controls upon oral STm infection. Our data identify a novel link between phagocytosis, inflammasome activity and autophagy in DCs, potentially explaining impaired antibacterial immunity in AP-3-deficient patients. PMID:29253868
iTRAQ protein profile analysis of Citrus sinensis roots in response to long-term boron-deficiency.

PubMed

Yang, Lin-Tong; Qi, Yi-Ping; Lu, Yi-Bin; Guo, Peng; Sang, Wen; Feng, Hui; Zhang, Hong-Xing; Chen, Li-Song

2013-11-20

Seedlings of Citrus sinensis were fertilized with boron (B)-deficient (0μM H3BO3) or -sufficient (10μM H3BO3) nutrient solution for 15weeks. Thereafter, iTRAQ analysis was employed to compare the abundances of proteins from B-deficient and -sufficient roots. In B-deficient roots, 164 up-regulated and 225 down-regulated proteins were identified. These proteins were grouped into the following functional categories: protein metabolism, nucleic acid metabolism, stress responses, carbohydrate and energy metabolism, cell transport, cell wall and cytoskeleton metabolism, biological regulation and signal transduction, and lipid metabolism. The adaptive responses of roots to B-deficiency might include following several aspects: (a) decreasing root respiration; (b) improving the total ability to scavenge reactive oxygen species (ROS); and (c) enhancing cell transport. The differentially expressed proteins identified by iTRAQ are much larger than those detected using 2D gel electrophoresis, and many novel B-deficiency-responsive proteins involved in cell transport, biological regulation and signal transduction, stress responses and other metabolic processes were identified in this work. Our results indicate remarkable metabolic flexibility of citrus roots, which may contribute to the survival of B-deficient plants. This represents the most comprehensive analysis of protein profiles in response to B-deficiency. In this study, we identified many new proteins involved in cell transport, biological regulation and signal transduction, stress responses and other metabolic processes that were not previously known to be associated with root B-deficiency responses. Therefore, our manuscript represents the most comprehensive analysis of protein profiles in response to B-deficiency and provides new information about the plant response to B-deficiency. This article is part of a Special Issue entitled: Translational Plant Proteomics. Copyright © 2013 Elsevier B.V. All rights reserved.
Common Filing Deficiencies in Abbreviated New Drug Applications Containing Clinical Endpoint Studies.

PubMed

Fermaglich, Lewis J; Chen, Ru; Kim, Carol Y; Chuh, Eunjung Esther; Thomas, Teena; Shetty, Daiva; Lee, Julia; Young, Johnny; Fan, Ying

2018-01-01

The objective of this report is to summarize common deficiencies identified in the filing reviews of abbreviated new drug applications (ANDAs) with clinical endpoint bioequivalence studies and skin irritation, sensitization, and adhesion (I/S/A) studies received by the US Food and Drug Administration (FDA) between 2007 and 2017, to help applicants avoid common deficiencies, minimize "refuse-to-receive" (RTR) actions, "information requests," and ANDA approval delays. Multiple internal FDA databases were searched to evaluate and summarize common deficiencies identified in ANDA submissions containing clinical endpoint studies and skin I/S/A studies that required review by the Division of Clinical Review. A total of 275 ANDA submissions with filing reviews from January 2007 to June 2017 were analyzed in this report. Two hundred eighteen (79.3%) filing reviews contained one or more deficiencies. Seventy-nine (28.7%) ANDAs were issued RTR letters because of major clinical deficiencies, specifically bioequivalence and clinical deficiencies, accounting for 9% of overall identified deficiencies. Twenty-two other categories of deficiencies are summarized into 4 main categories: missing information related to the clinical studies other than data sets (38%), missing data sets (35%), formulation issues (12%), and organization/format issues (6%). The most common deficiency in the "missing information related to the clinical studies other than data sets" category was "missing clarification of information" (22%). We also noted that the Division of Filing Review has identified these same types of deficiencies since assuming responsibility of the filing assessment for ANDAs with clinical endpoint BE studies and skin I/S/A studies. In conclusion, to minimize "refuse-to-receive" actions, "information requests," and approval of ANDA delays for generic drug products, applicants should submit full clinical study reports, including all data sets for drug products recommending clinical studies.
A method for identifying color vision deficiency malingering.

PubMed

Pouw, Andrew; Karanjia, Rustum; Sadun, Alfredo

2017-03-01

To propose a new test to identify color vision deficiency malingering. An online survey was distributed to 130 truly color vision deficient participants and 160 participants willing to simulate color vision deficiency. The survey contained three sets of six color-adjusted versions of the standard Ishihara color plates each, as well as one set of six control plates. The plates that best discriminated both participant groups were selected for a "balanced" test emphasizing both sensitivity and specificity. A "specific" test that prioritized high specificity was also created by selecting from these plates. Statistical measures of the test (sensitivity, specificity, and Youden index) were assessed at each possible cut-off threshold, and a receiver operating characteristic (ROC) function with its area under the curve (AUC) charted. The redshift plate set was identified as having the highest difference of means between groups (-58%, CI: -64 to -52%), as well as the widest gap between group modes. Statistical measures of the "balanced" test show an optimal cut-off of at least two incorrectly identified plates to suggest malingering (Youden index: 0.773, sensitivity: 83.3%, specificity: 94.0%, AUC of ROC 0.918). The "specific" test was able to identify color vision deficiency simulators with a specificity of 100% when using a cut-off of at least two incorrectly identified plates (Youden index 0.599, sensitivity 59.9%, specificity 100%, AUC of ROC 0.881). Our proposed test for identifying color vision deficiency malingering demonstrates a high degree of reliability with AUCs of 0.918 and 0.881 for the "balanced" and "specific" tests, respectively. A cut-off threshold of at least two missed plates on the "specific" test was able to identify color vision deficiency simulators with 100% specificity.
Nutrition Deficiencies in Children With Intestinal Failure Receiving Chronic Parenteral Nutrition.

PubMed

Namjoshi, Shweta S; Muradian, Sarah; Bechtold, Hannah; Reyen, Laurie; Venick, Robert S; Marcus, Elizabeth A; Vargas, Jorge H; Wozniak, Laura J

2017-02-01

Home parenteral nutrition (PN) is a lifesaving therapy for children with intestinal failure (IF). Our aims were to describe the prevalence of micronutrient deficiencies (vitamin D, zinc, copper, iron, selenium) in a diverse population of children with IF receiving PN and to identify and characterize risk factors associated with micronutrient deficiencies, including hematologic abnormalities. Data were collected on 60 eligible patients through retrospective chart review between May 2012 and February 2015. Descriptive statistics included frequencies, medians, interquartile ranges (IQRs), and odds ratios (ORs). Statistical analyses included χ 2 , Fisher's exact, t tests, and logistic, univariate, and multivariate regressions. Patients were primarily young (median age, 3.3 years; IQR, 0.7-8.4), Latino (62%), and male (56%), with short bowel syndrome (70%). Of 60 study patients, 88% had ≥1 deficiency and 90% were anemic for age. Of 51 patients who had all 5 markers checked, 59% had multiple deficiencies (defined as ≥3). Multivariate analysis shows multiple deficiencies were associated with nonwhite race (OR, 9.4; P = .012) and higher body mass index z score (OR, 2.2; P = .016). Children with severe anemia (hemoglobin <8.5 g/dL) made up 50% of the cohort. Nonwhite race (OR, 6.6; P = .037) and zinc deficiency (OR, 11; P = .003) were multivariate predictors of severe anemia. Micronutrient deficiency and anemia are overwhelmingly prevalent in children with IF using chronic PN. This emphasizes the importance of universal surveillance and supplementation to potentially improve quality of life and developmental outcomes. Future research should investigate how racial disparities might contribute to nutrition outcomes for children using chronic PN.
Vitamin D deficiency in Saudi Arabians: A reality or simply hype: A meta-analysis (2008-2015).

PubMed

Al-Alyani, Haneen; Al-Turki, Haifa A; Al-Essa, Omar N; Alani, Fawaz M; Sadat-Ali, Mir

2018-01-01

The objective of this systematic review was to determine from published data the prevalence of Vitamin D deficiency in the Saudi population. An extensive and meticulous search was conducted for studies published in MEDLINE, EMBASE the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (2008-2015), and the Science Citation Index published data from the Annals of Saudi Medicine and Saudi Medical Journal with the key words: Vitamin D deficiency, insufficiency, and Saudi Arabians. The inclusion criterion was studies published during 2008 to 2015, and studies involving healthy individuals between the age of 18 and 80 years. Binary random- effect model was used to estimate pooled Vitamin D deficiency. Prevalence rates along with overall estimate were presented by forest plot. Heterogeneity test was used to assess the significance of heterogeneity among studies. The authors identified 26 potentially relevant articles, 16 of which met the inclusion criteria. A total of 20,787 patients were analyzed. Sixty-two percent (12,959) were females, and the rest were males. The overall Vitamin D deficiency was 63.5% (95% CI: 53.3, 73.7). The currently available literature on the Saudi Arabian population suggests that the Vitamin D deficiency is around 60% and not 100% as indicated in some studies. The relatively small number of studies on the population and the different modes of diagnostic methodology used make the issue of correct figures of Vitamin D deficiency contentious.
Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1.

PubMed

Hinrichsen, Inga; Ernst, Benjamin Philipp; Nuber, Franziska; Passmann, Sandra; Schäfer, Dieter; Steinke, Verena; Friedrichs, Nicolaus; Plotz, Guido; Zeuzem, Stefan; Brieger, Angela

2014-01-24

Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1

PubMed Central

2014-01-01

Introduction Defects in the DNA mismatch repair (MMR) protein MLH1 are frequently observed in sporadic and hereditary colorectal cancers (CRC). Affected tumors generate much less metastatic potential than the MLH1 proficient forms. Although MLH1 has been shown to be not only involved in postreplicative MMR but also in several MMR independent processes like cytoskeletal organization, the connection between MLH1 and metastasis remains unclear. We recently identified non-erythroid spectrin αII (SPTAN1), a scaffolding protein involved in cell adhesion and motility, to interact with MLH1. In the current study, the interaction of MLH1 and SPTAN1 and its potential consequences for CRC metastasis was evaluated. Methods Nine cancer cell lines as well as fresh and paraffin embedded colon cancer tissue from 12 patients were used in gene expression studies of SPTAN1 and MLH1. Co-expression of SPTAN1 and MLH1 was analyzed by siRNA knock down of MLH1 in HeLa, HEK293, MLH1 positive HCT116, SW480 and LoVo cells. Effects on cellular motility were determined in MLH1 deficient HCT116 and MLH1 deficient HEK293T compared to their MLH1 proficient sister cells, respectively. Results MLH1 deficiency is clearly associated with SPTAN1 reduction. Moreover, siRNA knock down of MLH1 decreased the mRNA level of SPTAN1 in HeLa, HEK293 as well as in MLH1 positive HCT116 cells, which indicates a co-expression of SPTAN1 by MLH1. In addition, cellular motility of MLH1 deficient HCT116 and MLH1 deficient HEK293T cells was impaired compared to the MLH1 proficient sister clones. Consequently, overexpression of SPTAN1 increased migration of MLH1 deficient cells while knock down of SPTAN1 decreased cellular mobility of MLH1 proficient cells, indicating SPTAN1-dependent migration ability. Conclusions These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1. PMID:24456667
Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis.

PubMed

Ashrafian, Houman; O'Flaherty, Linda; Adam, Julie; Steeples, Violetta; Chung, Yuen-Li; East, Phil; Vanharanta, Sakari; Lehtonen, Heli; Nye, Emma; Hatipoglu, Emine; Miranda, Melroy; Howarth, Kimberley; Shukla, Deepa; Troy, Helen; Griffiths, John; Spencer-Dene, Bradley; Yusuf, Mohammed; Volpi, Emanuela; Maxwell, Patrick H; Stamp, Gordon; Poulsom, Richard; Pugh, Christopher W; Costa, Barbara; Bardella, Chiara; Di Renzo, Maria Flavia; Kotlikoff, Michael I; Launonen, Virpi; Aaltonen, Lauri; El-Bahrawy, Mona; Tomlinson, Ian; Pollard, Patrick J

2010-11-15

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that "pseudohypoxic" stabilization of hypoxia-inducible factor-α (HIF-α) by fumarate accumulation contributes to tumorigenesis in HLRCC. We hypothesized that an additional direct consequence of FH deficiency is the establishment of a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As predicted, these MEFs upregulated Hif-1α and HIF target genes directly as a result of FH deficiency. In addition, detailed metabolic assessment of these MEFs confirmed their dependence on glycolysis, and an elevated rate of lactate efflux, associated with the upregulation of glycolytic enzymes known to be associated with tumorigenesis. Correspondingly, Fh1-deficient benign murine renal cysts and an advanced human HLRCC-related renal cell carcinoma manifested a prominent and progressive increase in the expression of HIF-α target genes and in genes known to be relevant to tumorigenesis and metastasis. In accord with our hypothesis, in a variety of different FH-deficient tissues, including a novel murine model of Fh1-deficient smooth muscle, we show a striking and progressive upregulation of a tumorigenic metabolic profile, as manifested by increased PKM2 and LDHA protein. Based on the models assessed herein, we infer that that FH deficiency compels cells to adopt an early, reversible, and progressive protumorigenic metabolic milieu that is reminiscent of that driving the Warburg effect. Targets identified in these novel and diverse FH-deficient models represent excellent potential candidates for further mechanistic investigation and therapeutic metabolic manipulation in tumors. Copyright © 2010 AACR.
Peritumoral granulomatous reaction in endometrial carcinoma: association with DNA mismatch repair protein deficiency, particularly loss of PMS2 expression.

PubMed

Stewart, Colin J R; Pearn, Amy; Pachter, Nicholas; Tan, Adeline

2018-04-30

The observation of peritumoral granulomatous reactions (PGRs) in two endometrial carcinomas (ECs) with a PMS2-deficient/MLH1-intact expression pattern led us to investigate whether PGRs in EC were specifically associated with DNA mismatch repair (MMR) protein deficiency, particularly PMS2 loss. Hysterectomy specimens from 22 MMR protein-intact and 54 MMR protein-deficient ECs were reviewed with specific attention to the presence of a PGR and a tumour-associated lymphoid reaction [including tumour-infiltrating lymphocytes (TILs) and stromal lymphoid infiltrates]. The MMR protein-deficient ECs included 22 cases with combined MLH1/PMS2 loss, 11 with combined MSH2/MSH6 loss, 11 with isolated MSH6 loss, and 10 with PMS2 loss but intact MLH1 staining (including the two 'index' cases). Overall, PGRs were identified in seven of 54 (13%) MMR protein-deficient ECs, five of which showed a PMS2-deficient/MLH1-intact immunophenotype; three of these patients had germline PMS2 mutations and one additional patient had a germline MSH6 mutation. None of the MMR protein-intact tumours showed a PGR. Although five of the seven PGR-positive ECs had a high-grade histological component, six were stage I. Most ECs with PGRs also showed TILs and stromal lymphoid reactions, similarly to MMR protein-deficient ECs in general. MMR protein-deficient ECs, particularly those with PMS2 loss, occasionally show PGRs in addition to stromal lymphoid infiltrates and TILs. Therefore, PGRs could be considered to constitute a histological prompt for consideration of Lynch syndrome. The potential prognostic significance of PGRs in EC requires further study. © 2018 John Wiley & Sons Ltd.

Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

PubMed

Maletzki, Claudia; Huehns, Maja; Bauer, Ingrid; Ripperger, Tim; Mork, Maureen M; Vilar, Eduardo; Klöcking, Sabine; Zettl, Heike; Prall, Friedrich; Linnebacher, Michael

2017-07-01

Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis. © 2017 Wiley Periodicals, Inc.
Monocarboxylate transporter 1 deficiency and ketone utilization.

PubMed

van Hasselt, Peter M; Ferdinandusse, Sacha; Monroe, Glen R; Ruiter, Jos P N; Turkenburg, Marjolein; Geerlings, Maartje J; Duran, Karen; Harakalova, Magdalena; van der Zwaag, Bert; Monavari, Ardeshir A; Okur, Ilyas; Sharrard, Mark J; Cleary, Maureen; O'Connell, Nuala; Walker, Valerie; Rubio-Gozalbo, M Estela; de Vries, Maaike C; Visser, Gepke; Houwen, Roderick H J; van der Smagt, Jasper J; Verhoeven-Duif, Nanda M; Wanders, Ronald J A; van Haaften, Gijs

2014-11-13

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.
Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function

PubMed Central

Ivaskevicius, Vytautas; Biswas, Arijit; Bevans, Carville; Schroeder, Verena; Kohler, Hans Peter; Rott, Hannelore; Halimeh, Susan; Petrides, Petro E.; Lenk, Harald; Krause, Manuele; Miterski, Bruno; Harbrecht, Ursula; Oldenburg, Johannes

2010-01-01

Background Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. Design and Methods We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. Results All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. Conclusions The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms. PMID:20179087
Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function.

PubMed

Ivaskevicius, Vytautas; Biswas, Arijit; Bevans, Carville; Schroeder, Verena; Kohler, Hans Peter; Rott, Hannelore; Halimeh, Susan; Petrides, Petro E; Lenk, Harald; Krause, Manuele; Miterski, Bruno; Harbrecht, Ursula; Oldenburg, Johannes

2010-06-01

Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. We analyzed ten index patients and three relatives for factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. All individuals except one were heterozygous for factor XIIIA mutations (average factor XIII activity 51%), while the remaining homozygous individual was found to have severe factor XIII deficiency (<5% of normal factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the factor XIIIA protein. Future in vitro expression studies of the factor XIII mutations are required to confirm their pathological mechanisms.
NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

PubMed

Shi, Hongjun; Enriquez, Annabelle; Rapadas, Melissa; Martin, Ella M M A; Wang, Roni; Moreau, Julie; Lim, Chai K; Szot, Justin O; Ip, Eddie; Hughes, James N; Sugimoto, Kotaro; Humphreys, David T; McInerney-Leo, Aideen M; Leo, Paul J; Maghzal, Ghassan J; Halliday, Jake; Smith, Janine; Colley, Alison; Mark, Paul R; Collins, Felicity; Sillence, David O; Winlaw, David S; Ho, Joshua W K; Guillemin, Gilles J; Brown, Matthew A; Kikuchi, Kazu; Thomas, Paul Q; Stocker, Roland; Giannoulatou, Eleni; Chapman, Gavin; Duncan, Emma L; Sparrow, Duncan B; Dunwoodie, Sally L

2017-08-10

Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system. Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).
Identifying areas with vitamin A deficiency: the validity of a semiquantitative food frequency method.

PubMed

Sloan, N L; Rosen, D; de la Paz, T; Arita, M; Temalilwa, C; Solomons, N W

1997-02-01

The prevalence of vitamin A deficiency has traditionally been assessed through xerophthalmia or biochemical surveys. The cost and complexity of implementing these methods limits the ability of nonresearch organizations to identify vitamin A deficiency. This study examined the validity of a simple, inexpensive food frequency method to identify areas with a high prevalence of vitamin A deficiency. The validity of the method was tested in 15 communities, 5 each from the Philippines, Guatemala, and Tanzania. Serum retinol concentrations of less than 20 micrograms/dL defined vitamin A deficiency. Weighted measures of vitamin A intake six or fewer times per week and unweighted measures of consumption of animal sources of vitamin A four or fewer times per week correctly classified seven of eight communities as having a high prevalence of vitamin A deficiency (i.e., 15% or more preschool-aged children in the community had the deficiency) (sensitivity = 87.5%) and four of seven communities as having a low prevalence (specificity = 57.1%). This method correctly classified the vitamin A deficiency status of 73.3% of the communities but demonstrated a high false-positive rate (42.9%).
Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia

PubMed Central

He, Lijun; Li, Qing; Wu, Yanrui; Luo, Lan; Li, Hong; Ma, Limei; Yang, Zhaoqing; He, Yongshu; Cui, Liwang

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobin E (HbE, β26 Glu-Lys) are two common red cell disorders in Southeast Asia. G6PD deficiency produces hemolytic anemia, which can be triggered by certain drugs or infections. HbE is asymptomatic or is manifested as microcytic, minimally hemolytic anemia. The association between G6PD deficiency and HbE is little understood. This study aimed to investigate G6PD deficiency and HbE in a Kachin ethnic group in the China-Myanmar border area. G6PD enzyme activity was measured using a quantitative G6PD assay, G6PD variants genotyped by the SNaPshot assay, and an HbE gene mutation identified by an amplification refractory mutation system and subsequently confirmed by using a reverse dot blot hybridization assay from 100 unrelated individuals in the study area. G6PD enzyme activity ranged from 0.4 to 24.7 U/g Hb, and six males had severe G6PD deficiency (<0.12–1.2 U/g Hb), while six males and 12 females had mild G6PD deficiency (>1.2–4.5 U/g Hb). Among the 24 G6PD-deficient subjects, 22 (92%) had the Mahidol 487G>A mutation (12 male hemizygotes, one female homozygote, and nine female heterozygotes), while the G6PD genotypes in two female subjects were unknown. HbE was identified in 39 subjects (20 males and 19 females), including 15 HbEE (seven males and eight females) and 24 HbAE (13 males and 11 females). Twenty-three subjects co-inherited both G6PD deficiency and HbE (22 with HbAE and one with HbEE). Whereas mean Hb levels were not significantly different between the HbA and HbE groups, G6PD-deficient males had significantly lower Hb levels than G6PD-normal males (P < 0.05, t-test). However, it is noteworthy that two G6PD-deficient hemizygous males with HbAE were severely anemic with Hb levels below 50 g/L. This study revealed high prevalence of co-inheritance of G6PD deficiency with HbAE in the Kachin ethnicity, and a potential interaction of the G6PD Mahidol 487G>A and HbAE in males leading to severe anemia. The presence of 6% males with severe G6PD deficiency raised a major concern in the use of primaquine for radical cure of vivax malaria. PMID:28531196
Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia.

PubMed

Deng, Zeshuai; Yang, Fang; Bai, Yao; He, Lijun; Li, Qing; Wu, Yanrui; Luo, Lan; Li, Hong; Ma, Limei; Yang, Zhaoqing; He, Yongshu; Cui, Liwang

2017-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobin E (HbE, β26 Glu-Lys) are two common red cell disorders in Southeast Asia. G6PD deficiency produces hemolytic anemia, which can be triggered by certain drugs or infections. HbE is asymptomatic or is manifested as microcytic, minimally hemolytic anemia. The association between G6PD deficiency and HbE is little understood. This study aimed to investigate G6PD deficiency and HbE in a Kachin ethnic group in the China-Myanmar border area. G6PD enzyme activity was measured using a quantitative G6PD assay, G6PD variants genotyped by the SNaPshot assay, and an HbE gene mutation identified by an amplification refractory mutation system and subsequently confirmed by using a reverse dot blot hybridization assay from 100 unrelated individuals in the study area. G6PD enzyme activity ranged from 0.4 to 24.7 U/g Hb, and six males had severe G6PD deficiency (<0.12-1.2 U/g Hb), while six males and 12 females had mild G6PD deficiency (>1.2-4.5 U/g Hb). Among the 24 G6PD-deficient subjects, 22 (92%) had the Mahidol 487G>A mutation (12 male hemizygotes, one female homozygote, and nine female heterozygotes), while the G6PD genotypes in two female subjects were unknown. HbE was identified in 39 subjects (20 males and 19 females), including 15 HbEE (seven males and eight females) and 24 HbAE (13 males and 11 females). Twenty-three subjects co-inherited both G6PD deficiency and HbE (22 with HbAE and one with HbEE). Whereas mean Hb levels were not significantly different between the HbA and HbE groups, G6PD-deficient males had significantly lower Hb levels than G6PD-normal males (P < 0.05, t-test). However, it is noteworthy that two G6PD-deficient hemizygous males with HbAE were severely anemic with Hb levels below 50 g/L. This study revealed high prevalence of co-inheritance of G6PD deficiency with HbAE in the Kachin ethnicity, and a potential interaction of the G6PD Mahidol 487G>A and HbAE in males leading to severe anemia. The presence of 6% males with severe G6PD deficiency raised a major concern in the use of primaquine for radical cure of vivax malaria.
The impact of phenotypic and genotypic G6PD deficiency on risk of plasmodium vivax infection: a case-control study amongst Afghan refugees in Pakistan.

PubMed

Leslie, Toby; Briceño, Marnie; Mayan, Ismail; Mohammed, Nasir; Klinkenberg, Eveline; Sibley, Carol Hopkins; Whitty, Christopher J M; Rowland, Mark

2010-05-25

The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A-) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection. A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06-0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02-0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15-0.94], p = 0.037). G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.
ENU Mutagenesis in Mice Identifies Candidate Genes For Hypogonadism

PubMed Central

Weiss, Jeffrey; Hurley, Lisa A.; Harris, Rebecca M.; Finlayson, Courtney; Tong, Minghan; Fisher, Lisa A.; Moran, Jennifer L.; Beier, David R.; Mason, Christopher; Jameson, J. Larry

2012-01-01

Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low density genome-wide SNP arrays. Ten of the fifteen lines were pursued further using higher resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility. PMID:22258617
Lack of association between the pseudo deficiency mutation in the arylsulfatase A gene on chromosome 22 with schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, P.L.; Chetty, V.; Kasch, L.

Arylsulfatase-A deficiency causes the neurodegenerative lysosomal storage disease metachromatic leukodystrophy. In the late-onset variant, schizophrenia-like psychosis is a frequent finding and sometimes given as the initial diagnosis. A mutant allele, pseudo-deficiency, causes deficient enzyme activity but no apparent clinical effect. It occurs at a high frequency and consists of two tightly-linked A{r_arrow}G transitions: one causing the loss of a glycosylation site (PDg); and one causing the loss of a polyadenylation signal (PDa). Since this gene was mapped to chromosome 22q13-qter, a region implicated in a potential linkage with schizophrenia, we hypothesized that this common mutation may be a predisposing geneticmore » factor for schizophrenia. We studied a random sample of schizophrenic patients for possible increase in frequency of the pseudo-deficiency mutations and in multiplex families to verify if the mutations are linked to schizophrenia. Among 50 Caucasian patients identified through out-patient and in-patient clinics, the frequencies for the three alleles PDg + PDa together, PDg or PDa alone were 11%, 5% and 0%, respectively. The corresponding frequencies among 100 Caucasian controls were 7.5%, 6% and 0%, respectively, the differences between the patients and controls being insignificant ({chi}{sup 2}tests: 0.10« less
Sociodemographic and cultural determinants of sleep deficiency: implications for cardiometabolic disease risk.

PubMed

Knutson, Kristen L

2013-02-01

Sleep is a biological imperative associated with cardiometabolic disease risk. As such, a thorough discussion of the sociocultural and demographic determinants of sleep is warranted, if not overdue. This paper begins with a brief review of the laboratory and epidemiologic evidence linking sleep deficiency, which includes insufficient sleep and poor sleep quality, with increased risk of chronic cardiometabolic diseases such as obesity, diabetes and hypertension. Identification of the determinants of sleep deficiency is the critical next step to understanding the role sleep plays in human variation in health and disease. Therefore, the majority of this paper describes the different biopsychosocial determinants of sleep, including age, gender, psychosocial factors (depression, stress and loneliness), socioeconomic position and race/ethnicity. In addition, because sleep duration is partly determined by behavior, it will be shaped by cultural values, beliefs and practices. Therefore, possible cultural differences that may impact sleep are discussed. If certain cultural, ethnic or social groups are more likely to experience sleep deficiency, then these differences in sleep could increase their risk of cardiometabolic diseases. Furthermore, if the mechanisms underlying the increased risk of sleep deficiency in certain populations can be identified, interventions could be developed to target these mechanisms, reduce sleep differences and potentially reduce cardiometabolic disease risk. Copyright © 2012 Elsevier Ltd. All rights reserved.
Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-β-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease.

PubMed

Bi, Yiling; Might, Matthew; Vankayalapati, Hariprasad; Kuberan, Balagurunathan

2017-07-01

N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears. Unfortunately, there has not been any therapeutic option available for this rare disease so far. Recently, a proposed molecular mechanism for NGLY1 deficiency suggested that endo-β-N-acetylglucosaminidase (ENGase) inhibitors may be promising therapeutics for NGLY1 patients. Herein, we performed structure-based virtual screening utilizing FDA-approved drug database on this ENGase target to enable repurposing of existing drugs. Several Proton Pump Inhibitors (PPIs), a series of substituted 1H-benzo [d] imidazole, and 1H-imidazo [4,5-b] pyridines, among other scaffolds, have been identified as potent ENGase inhibitors. An electrophoretic mobility shift assay was employed to assess the inhibition of ENGase activity by these PPIs. Our efforts led to the discovery of Rabeprazole Sodium as the most promising hit with an IC 50 of 4.47±0.44μM. This is the first report that describes the discovery of small molecule ENGase inhibitors, which can potentially be used for the treatment of human NGLY1 deficiency. Copyright © 2017 Elsevier Ltd. All rights reserved.
IC 4663: The First Unambiguous [WN] Wolf-Rayet Central Star of a Planetary Nebula

NASA Astrophysics Data System (ADS)

Miszalski, B.; Crowther, P. A.; De Marco, O.; Köppen, J.; Moffat, A. F. J.; Acker, A.; Hillwig, T. C.

2013-01-01

Several [WC]-type central stars of planetary nebulae (PNe) are known to mimic the spectroscopic appearance of massive carbon-rich or WC-type Wolf-Rayet stars. In stark contrast, no [WN]-type central stars have yet been identified as clear-cut analogues of the common nitrogen-rich or WN-type Wolf-Rayet stars. We have identified the [WN3] central star of IC 4663 to be the first unambiguous example in PNe. The low luminosity nucleus and an asymptotic giant branch (AGB) halo surrounding the main nebula prove the bona-fide PN nature of IC 4663. Model atmosphere analysis reveals the [WN3] star to have an exotic chemical composition of helium (95%), hydrogen (<2%), nitrogen (0.8%), neon (0.2%) and oxygen (0.05%) by mass. Such an extreme helium-dominated composition cannot be predicted by current evolutionary scenarios for hydrogen deficient [WC]-type central stars. Only with the discovery of IC 4663 and its unusual composition can we now connect [WN] central stars to the O(He) central stars in a second H-deficient and He-rich evolutionary sequence, [WN]→O(He), that exists in parallel to the carbon-rich [WC]→PG1159 sequence. This suggests a simpler mechanism, perhaps a binary merger, can better explain H-deficiency in PNe and potentially other H-deficient/He-rich stars. In this respect IC 4663 is the best supported case for a possible merged binary central star of a PN.
Biomarkers of Nutrition for Development (BOND)—Zinc Review12345

PubMed Central

King, Janet C; Brown, Kenneth H; Gibson, Rosalind S; Krebs, Nancy F; Lowe, Nicola M; Siekmann, Jonathan H; Raiten, Daniel J

2016-01-01

Zinc is required for multiple metabolic processes as a structural, regulatory, or catalytic ion. Cellular, tissue, and whole-body zinc homeostasis is tightly controlled to sustain metabolic functions over a wide range of zinc intakes, making it difficult to assess zinc insufficiency or excess. The BOND (Biomarkers of Nutrition for Development) Zinc Expert Panel recommends 3 measurements for estimating zinc status: dietary zinc intake, plasma zinc concentration (PZC), and height-for-age of growing infants and children. The amount of dietary zinc potentially available for absorption, which requires an estimate of dietary zinc and phytate, can be used to identify individuals and populations at risk of zinc deficiency. PZCs respond to severe dietary zinc restriction and to zinc supplementation; they also change with shifts in whole-body zinc balance and clinical signs of zinc deficiency. PZC cutoffs are available to identify individuals and populations at risk of zinc deficiency. However, there are limitations in using the PZC to assess zinc status. PZCs respond less to additional zinc provided in food than to a supplement administered between meals, there is considerable interindividual variability in PZCs with changes in dietary zinc, and PZCs are influenced by recent meal consumption, the time of day, inflammation, and certain drugs and hormones. Insufficient data are available on hair, urinary, nail, and blood cell zinc responses to changes in dietary zinc to recommend these biomarkers for assessing zinc status. Of the potential functional indicators of zinc, growth is the only one that is recommended. Because pharmacologic zinc doses are unlikely to enhance growth, a growth response to supplemental zinc is interpreted as indicating pre-existing zinc deficiency. Other functional indicators reviewed but not recommended for assessing zinc nutrition in clinical or field settings because of insufficient information are the activity or amounts of zinc-dependent enzymes and proteins and biomarkers of oxidative stress, inflammation, or DNA damage. PMID:26962190
Autosomal recessive PGM3 mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment

PubMed Central

Zhang, Yu; Yu, Xiaomin; Ichikawa, Mie; Lyons, Jonathan J.; Datta, Shrimati; Lamborn, Ian T.; Jing, Huie; Kim, Emily S.; Biancalana, Matthew; Wolfe, Lynne A.; DiMaggio, Thomas; Matthews, Helen F.; Kranick, Sarah M.; Stone, Kelly D.; Holland, Steven M.; Reich, Daniel S.; Hughes, Jason D.; Mehmet, Huseyin; McElwee, Joshua; Freeman, Alexandra F.; Freeze, Hudson H.; Su, Helen C.; Milner, Joshua D.

2014-01-01

Background Identifying genetic syndromes that lead to significant atopic disease can open new pathways for investigation and intervention in allergy. Objective To define a genetic syndrome of severe atopy, elevated serum IgE, immune deficiency, autoimmunity, and motor and neurocognitive impairment. Methods Eight patients from two families who had similar syndromic features were studied. Thorough clinical evaluations, including brain MRI and sensory evoked potentials, were performed. Peripheral lymphocyte flow cytometry, antibody responses, and T cell cytokine production were measured. Whole exome sequencing was performed to identify disease-causing mutations. Immunoblotting, qRT-PCR, enzymatic assays, nucleotide sugar and sugar phosphate analyses along with MALDI-TOF mass spectrometry of glycans were used to determine the molecular consequences of the mutations. Results Marked atopy and autoimmunity were associated with increased TH2 and TH17 cytokine production by CD4+ T cells. Bacterial and viral infection susceptibility were noted along with T cell lymphopenia, particularly of CD8+ T cells, and reduced memory B cells. Apparent brain hypomyelination resulted in markedly delayed evoked potentials and likely contributed to neurological abnormalities. Disease segregated with novel autosomal recessive mutations in a single gene, phosphoglucomutase 3 (PGM3). Although PGM3 protein expression was variably diminished, impaired function was demonstrated by decreased enzyme activity and reduced UDP-GlcNAc, along with decreased O- and N-linked protein glycosylation in patients’ cells. These results define a new Congenital Disorder of Glycosylation. Conclusions Autosomal recessive, hypomorphic PGM3 mutations underlie a disorder of severe atopy, immune deficiency, autoimmunity, intellectual disability and hypomyelination. PMID:24589341
Nutrient deficiencies associated with nutrition-focused physical findings of the oral cavity.

PubMed

Radler, Diane Rigassio; Lister, Tracy

2013-12-01

Conducting nutrition-focused physical examinations and reporting the findings from the perspective of nutrition status strengthen the practitioner's assessments, interventions, and monitoring. The nutrition-focused physical examination of the oral cavity is particularly useful to identify nutrient deficiencies early and with accuracy as the tissues in the oral mucosa have a turnover rate of <1 week. As biomarkers may not always be reliable for identifying micronutrient deficiencies, these physical examinations are important for providing comprehensive nutrition care. The purpose of this article is to discuss the methods of conducting a nutrition-focused oral screening examination and compile and document the evidence regarding the effects of micronutrient deficiencies on the oral mucosa. The information is formatted into a table that can be used as a tool when conducting an oral screening by identifying possible deficiencies based on the observations and other relevant findings. The tool will also guide the practitioner in confirming the physical findings, suggesting interventions to treat the deficiency and how to monitor the outcomes.
Physiological, Ultrastructural and Proteomic Responses in the Leaf of Maize Seedlings to Polyethylene Glycol-Stimulated Severe Water Deficiency

PubMed Central

Shao, Ruixin; Xin, Longfei; Mao, Jun; Li, Leilei; Kang, Guozhang; Yang, Qinghua

2015-01-01

After maize seedlings grown in full-strength Hoagland solution for 20 days were exposed to 20% polyethylene glycol (PEG)-stimulated water deficiency for two days, plant height, shoot fresh and dry weights, and pigment contents significantly decreased, whereas malondialdehyde (MDA) content greatly increased. Using transmission electron microscopy, we observed that chloroplasts of mesophyll cells in PEG-treated maize seedlings were swollen, with a disintegrating envelope and disrupted grana thylakoid lamellae. Using two-dimensional gel electrophoresis (2-DE) method, we were able to identify 22 protein spots with significantly altered abundance in the leaves of treated seedlings in response to water deficiency, 16 of which were successfully identified. These protein species were functionally classified into signal transduction, stress defense, carbohydrate metabolism, protein metabolism, and unknown categories. The change in the abundance of the identified protein species may be closely related to the phenotypic and physiological changes due to PEG-stimulated water deficiency. Most of the identified protein species were putatively located in chloroplasts, indicating that chloroplasts may be prone to damage by PEG stimulated-water deficiency in maize seedlings. Our results help clarify the molecular mechanisms of the responses of higher plants to severe water deficiency. PMID:26370980
Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice

PubMed Central

Otten, Jeroen J. T.; de Jager, Saskia C. A.; Kavelaars, Annemieke; Seijkens, Tom; Bot, Ilze; Wijnands, Erwin; Beckers, Linda; Westra, Marijke M.; Bot, Martine; Busch, Matthias; Bermudez, Beatriz; van Berkel, Theo J. C.; Heijnen, Cobi J.; Biessen, Erik A. L.

2013-01-01

Leukocyte chemotaxis is deemed instrumental in initiation and progression of atherosclerosis. It is mediated by G-protein-coupled receptors (e.g., CCR2 and CCR5), the activity of which is controlled by G-protein-coupled receptor kinases (GRKs). In this study, we analyzed the effect of hematopoietic deficiency of a potent regulator kinase of chemotaxis (GRK2) on atherogenesis. LDL receptor-deficient (LDLr−/−) mice with heterozygous hematopoietic GRK2 deficiency, generated by bone marrow transplantation (n=15), displayed a dramatic attenuation of plaque development, with 79% reduction in necrotic core and increased macrophage content. Circulating monocytes decreased and granulocytes increased in GRK2+/− chimeras, which could be attributed to diminished granulocyte colony-forming units in bone marrow. Collectively, these data pointed to myeloid cells as major mediators of the impaired atherogenic response in GRK2+/− chimeras. LDLr−/− mice with macrophage/granulocyte-specific GRK2 deficiency (LysM-Cre GRK2flox/flox; n=8) failed to mimic the aforementioned phenotype, acquitting these cells as major responsible subsets for GRK2 deficiency-associated atheroprotection. To conclude, even partial hematopoietic GRK2 deficiency prevents atherosclerotic lesion progression beyond the fatty streak stage, identifying hematopoietic GRK2 as a potential target for intervention in atherosclerosis.—Otten, J. J. T., de Jager, S. C. A., Kavelaars, A., Seijkens, T., Bot, I., Wijnands, E., Beckers, L., Westra, M. M., Bot, M., Busch, M., Bermudez, B., van Berkel, T. J. C., Heijnen, C. J., Biessen, E. A. L. Hematopoietic G-protein-coupled receptor kinase 2 deficiency decreases atherosclerotic lesion formation in LDL receptor-knockout mice. PMID:23047899
DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome.

PubMed

Pai, Rish K; Dudley, Beth; Karloski, Eve; Brand, Randall E; O'Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D; Jenkins, Mark A; Thibodeau, Stephen N; French, Amy J; Lindor, Noralane M; Pai, Reetesh K

2018-06-08

Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and "Lynch-like" syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p < 0.001). This one patient had "Lynch-like" syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

PubMed Central

Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

2015-01-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states. PMID:26154191
Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency.

PubMed

Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

2015-07-08

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer's disease and Parkinson's disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.
Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

NASA Astrophysics Data System (ADS)

Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

2015-07-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.
Glucose-6-Phosphate Dehydrogenase-Deficiency in Transfusion Medicine: The Unknown Risks

PubMed Central

Francis, Richard O.; Jhang, Jeffrey S.; Pham, Huy P.; Hod, Eldad A.; Zimring, James C.; Spitalnik, Steven L.

2013-01-01

The hallmark of glucose-6-phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce hemolysis in G6PD-deficient RBCs. Although it is not routine practice to screen healthy blood donors for G6PD deficiency, case reports identified transfusion of G6PD-deficient RBCs as causing hemolysis and other adverse events. In addition, some patient populations may be more at risk for complications associated with transfusions of G6PD-deficient RBCs because they receive RBCs from donors who are more likely to have G6PD deficiency. This review discusses G6PD deficiency, its importance in transfusion medicine, changes in the RBC antioxidant system (of which G6PD is essential) during refrigerated storage, and mechanisms of hemolysis. In addition, as yet unanswered questions that could be addressed by translational and clinical studies are identified and discussed. PMID:23815264
Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

PubMed Central

Cloonan, Suzanne M.; Glass, Kimberly; Laucho-Contreras, Maria E.; Bhashyam, Abhiram R.; Cervo, Morgan; Pabón, Maria A.; Konrad, Csaba; Polverino, Francesca; Siempos, Ilias I.; Perez, Elizabeth; Mizumura, Kenji; Ghosh, Manik C.; Parameswaran, Harikrishnan; Williams, Niamh C.; Rooney, Kristen T.; Chen, Zhi-Hua; Goldklang, Monica P.; Yuan, Guo-Cheng; Moore, Stephen C.; Demeo, Dawn L.; Rouault, Tracey A.; D’Armiento, Jeanine M.; Schon, Eric A.; Manfredi, Giovanni; Quackenbush, John; Mahmood, Ashfaq; Silverman, Edwin K.; Owen, Caroline A.; Choi, Augustine M.K.

2015-01-01

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. PMID:26752519
Boron-deficiency-responsive microRNAs and their targets in Citrus sinensis leaves.

PubMed

Lu, Yi-Bin; Qi, Yi-Ping; Yang, Lin-Tong; Guo, Peng; Li, Yan; Chen, Li-Song

2015-11-04

MicroRNAs play important roles in the adaptive responses of plants to nutrient deficiencies. Most research, however, has focused on nitrogen (N), phosphorus (P), sulfur (S), copper (Cu) and iron (Fe) deficiencies, limited data are available on the differential expression of miRNAs and their target genes in response to deficiencies of other nutrient elements. In this study, we identified the known and novel miRNAs as well as the boron (B)-deficiency-responsive miRNAs from citrus leaves in order to obtain the potential miRNAs related to the tolerance of citrus to B-deficiency. Seedlings of 'Xuegan' [Citrus sinensis (L.) Osbeck] were supplied every other day with B-deficient (0 μM H3BO3) or -sufficient (10 μM H3BO3) nutrient solution for 15 weeks. Thereafter, we sequenced two small RNA libraries from B-deficient and -sufficient (control) citrus leaves, respectively, using Illumina sequencing. Ninety one (83 known and 8 novel) up- and 81 (75 known and 6 novel) down-regulated miRNAs were isolated from B-deficient leaves. The great alteration of miRNA expression might contribute to the tolerance of citrus to B-deficiency. The adaptive responses of miRNAs to B-deficiency might related to several aspects: (a) attenuation of plant growth and development by repressing auxin signaling due to decreased TIR1 level and ARF-mediated gene expression by altering the expression of miR393, miR160 and miR3946; (b) maintaining leaf phenotype and enhancing the stress tolerance by up-regulating NACs targeted by miR159, miR782, miR3946 and miR7539; (c) activation of the stress responses and antioxidant system through down-regulating the expression of miR164, miR6260, miR5929, miR6214, miR3946 and miR3446; (d) decreasing the expression of major facilitator superfamily protein genes targeted by miR5037, thus lowering B export from plants. Also, B-deficiency-induced down-regulation of miR408 might play a role in plant tolerance to B-deficiency by regulating Cu homeostasis and enhancing superoxide dismutase activity. Our study reveals some novel responses of citrus to B-deficiency, which increase our understanding of the adaptive mechanisms of citrus to B-deficiency at the miRNA (post-transcriptional) level.
Indicator organisms in meat and poultry slaughter operations: their potential use in process control and the role of emerging technologies.

PubMed

Saini, Parmesh K; Marks, Harry M; Dreyfuss, Moshe S; Evans, Peter; Cook, L Victor; Dessai, Uday

2011-08-01

Measuring commonly occurring, nonpathogenic organisms on poultry products may be used for designing statistical process control systems that could result in reductions of pathogen levels. The extent of pathogen level reduction that could be obtained from actions resulting from monitoring these measurements over time depends upon the degree of understanding cause-effect relationships between processing variables, selected output variables, and pathogens. For such measurements to be effective for controlling or improving processing to some capability level within the statistical process control context, sufficiently frequent measurements would be needed to help identify processing deficiencies. Ultimately the correct balance of sampling and resources is determined by those characteristics of deficient processing that are important to identify. We recommend strategies that emphasize flexibility, depending upon sampling objectives. Coupling the measurement of levels of indicator organisms with practical emerging technologies and suitable on-site platforms that decrease the time between sample collections and interpreting results would enhance monitoring process control.
Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice.

PubMed

Walsh, Ryan M; Shen, Erica Y; Bagot, Rosemary C; Anselmo, Anthony; Jiang, Yan; Javidfar, Behnam; Wojtkiewicz, Gregory J; Cloutier, Jennifer; Chen, John W; Sadreyev, Ruslan; Nestler, Eric J; Akbarian, Schahram; Hochedlinger, Konrad

2017-05-09

PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of PHF8 have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a Phf8 knockout allele in mice to examine the consequences of Phf8 loss for development and behaviour. Phf8 deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of Phf8. We further observe misregulation of serotonin signalling within the prefrontal cortex of Phf8 deficient mice and identify the serotonin receptors Htr1a and Htr2a as direct targets of PHF8. Our results clarify the functional role of Phf8 in mammalian development and behaviour and establish a direct link between Phf8 expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.
Nursing home consumer complaints and their potential role in assessing quality of care.

PubMed

Stevenson, David G

2005-02-01

State survey agencies collect and investigate consumer complaints for care in nursing homes and other health care settings. Complaint investigations play a key role in quality assurance, because they can respond to concerns of consumers and families. This study uses 5 years of nursing home complaints data from Massachusetts (1998-2002) to investigate whether complaints might be used to assess nursing home quality of care. The investigator matches facility-level complaints data with On-Line Survey Certification and Reporting (OSCAR) data and Minimum Data Set Quality Indicator (MDS QI) data to evaluate the association between consumer complaints, facility and resident characteristics, and other nursing home quality measures. Consumer complaints varied across facility characteristics in ways consistent with the nursing home quality literature. Complaints were consistently and significantly associated with survey deficiencies, the presence of a serious survey deficiency, and nurse aide staffing. Complaints were not significantly associated with nurse staffing, and associations with 6 MDS QIs were mixed. The number of complaints was significantly predictive of survey deficiencies identified at the subsequent inspection. Nursing home consumer complaints provide a supplemental tool with which to differentiate nursing homes on quality. Despite limitations, complaints data have potential strengths when used in combination with other quality measures. The potential of using consumer complaints to assess nursing home quality of care should be evaluated in states beyond Massachusetts. Evaluating consumer complaints also might be a productive area of inquiry for other health care settings such as hospitals and home health agencies.
Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests.

PubMed

Wang, Li-Yun; Chen, Nien-I; Chen, Pin-Wen; Chiang, Shu-Chuan; Hwu, Wuh-Liang; Lee, Ni-Chung; Chien, Yin-Hsiu

2013-02-10

Tandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate. Three mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs). The results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate. Utilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.
Short stature before puberty: which children should be screened for SHOX deficiency?

PubMed

Wolters, Barbara; Lass, Nina; Wunsch, Rainer; Böckmann, Beatrix; Austrup, Frank; Reinehr, Thomas

2013-01-01

We studied the prevalence of deficiency in the short stature homeobox containing gene (SHOX) in prepubertal short-statured children and analyzed the clinical and radiological signs. Screening for SHOX deficiency was performed in 449 prepubertal short-statured children (54% females, aged 4-10 years) by direct sequencing and multiplex ligation probe-dependent amplification. Children with SHOX deficiency were compared to 1:2 age- and gender-matched prepubertal children without SHOX deficiency with respect to left-hand radiographs and anthropometrics including different ratios to height and proposed scores. We identified 22 (4.9%) patients with SHOX deficiency (64% point mutations). Children with SHOX deficiency demonstrated a mesomelic shortening of extremities. Lower leg lengths but not forearm length was reduced in children <8 years with SHOX deficiency. 36% of all children and none of the children <8 years with SHOX deficiency demonstrated any typical radiologic sign. Increased sitting height-to-height ratio and decreased extremities-to-trunk ratio demonstrated the best positive and negative predictive values to identify SHOX deficiency. Screening for SHOX deficiency seems rational, especially in children with increased sitting height-to-height ratio or decreased extremities-to-trunk ratio. These criteria were also valid in young children. © 2013 S. Karger AG, Basel.
Transmitter release in the neuromuscular synapse of the protein kinase C theta-deficient adult mouse.

PubMed

Besalduch, Núria; Santafé, Manel M; Garcia, Neus; Gonzalez, Carmen; Tomás, Marta; Tomás, Josep; Lanuza, Maria A

2011-04-01

We studied structural and functional features of the neuromuscular junction in adult mice (P30) genetically deficient in the protein kinase C (PKC) theta isoform. Confocal and electron microscopy shows that there are no differences in the general morphology of the endplates between PKC theta-deficient and wild-type (WT) mice. Specifically, there is no difference in the density of the synaptic vesicles. However, the myelin sheath is not as thick in the intramuscular nerve fibers of the PKC theta-deficient mice. We found a significant reduction in the size of evoked endplate potentials and in the frequency of spontaneous, asynchronous, miniature endplate potentials in the PKC theta-deficient neuromuscular preparations in comparison with the WT, but the mean amplitude of the spontaneous potentials is not different. These changes indicate that PKC theta has a presynaptic role in the function of adult neuromuscular synapses. Copyright © 2010 Wiley-Liss, Inc.
An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.

PubMed

Bhaskar, Vinay; Goldfine, Ira D; Gerstner, Resi; Michelson, Kristen; Tran, Catarina; Nonet, Genevieve; Bohmann, David; Pongo, Elizabeth; Zhao, Jingsong; Horwitz, Arnold H; Takeuchi, Toshihiko; White, Mark; Corbin, John A

2016-08-01

Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half-life and low immunogenicity could be useful in the treatment of this condition. Phage display technology coupled with flow cytometry and cell-based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP-deficient Lep(ob) /Lep(ob) mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured. XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep(ob) /Lep(ob) mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects. Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency. © 2016 The Obesity Society.
ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer.

PubMed

Drosos, Yiannis; Escobar, David; Chiang, Ming-Yi; Roys, Kathryn; Valentine, Virginia; Valentine, Marc B; Rehg, Jerold E; Sahai, Vaibhav; Begley, Lesa A; Ye, Jianming; Paul, Leena; McKinnon, Peter J; Sosa-Pineda, Beatriz

2017-09-11

Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras G12D ). We show that partial or total ATM deficiency cooperates with Kras G12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16 Ink4a and p19 Arf . However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.
The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan

PubMed Central

Leslie, Toby; Briceño, Marnie; Mayan, Ismail; Mohammed, Nasir; Klinkenberg, Eveline; Sibley, Carol Hopkins; Whitty, Christopher J. M.; Rowland, Mark

2010-01-01

Background The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir. The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum. Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations. The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine). If the level of protection was sufficient, antirelapse therapy could become more widely available. We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection. Methods and Findings A case-control study design was used amongst Afghan refugees in Pakistan. The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years. Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06–0.52], p = 0.001). Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02–0.92], p = 0.041). The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15–0.94], p = 0.037). Conclusions G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations. Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy. Please see later in the article for the Editors' Summary PMID:20520804
The prevalence of glucose-6-phosphate dehydrogenase deficiency in Gambian school children.

PubMed

Okebe, Joseph; Amambua-Ngwa, Alfred; Parr, Jason; Nishimura, Sei; Daswani, Melissa; Takem, Ebako N; Affara, Muna; Ceesay, Serign J; Nwakanma, Davis; D'Alessandro, Umberto

2014-04-17

Primaquine, the only available drug effective against Plasmodium falciparum sexual stages, induces also a dose-dependent haemolysis, especially in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals. Therefore, it is important to determine the prevalence of this deficiency in areas that would potentially benefit from its use. The prevalence of G6PD deficiency by genotype and enzyme activity was determined in healthy school children in The Gambia. Blood samples from primary school children collected during a dry season malaria survey were screened for G6PDd and malaria infection. Genotypes for allele mutations reported in the country; 376, 202A-, 968A- and 542 were analysed while enzyme activity (phenotype) was assayed using a semi-quantitative commercial test kit. Enzyme activity values were fitted in a finite mixture model to determine the distribution and calculate a cut-off for deficiency. The association between genotype and phenotype for boys and girls as well as the association between mutant genotype and deficient phenotype was analysed. Samples from 1,437 children; 51% boys were analysed. The prevalence of P. falciparum malaria infection was 14%. The prevalence of the 202A-, 968 and 542 mutations was 1.8%, 2.1% and 1.0%, respectively, and higher in boys than in girls. The prevalence of G6PDd phenotype was 6.4% (92/1,437), 7.8% (57/728) in boys and 4.9% (35/709) in girls with significantly higher odds in the former (OR 1.64, 95% CI 1.05, 2.53, p = 0.026). The deficient phenotype was associated with reduced odds of malaria infection (OR 0.77, 95% CI 0.36, 1.62, p = 0.49). There is a weak association between genotype and phenotype estimates of G6PDd prevalence. The phenotype expression of deficiency represents combinations of mutant alleles rather than specific mutations. Genotype studies in individuals with a deficient phenotype would help identify alleles responsible for haemolysis.
Dietary deficiency of vitamin A among rural children: A community-based survey using a food-frequency questionnaire.

PubMed

Suri, Shivali; Kumar, Dinesh; Das, Ranjan

2017-01-01

Overt vitamin A deficiency has been controlled in most parts of India, but prevalence of subclinical deficiency may still be high, which may enhance susceptibility to infections, reduce growth potential and also lead to higher mortality. We aimed to: (i) assess the consumption pattern of vitamin A-rich foods in children 1-5 years of age in rural Jammu; and (ii) estimate the dietary deficiency of vitamin A leading to risk of subclinical vitamin A deficiency in cluster- villages of the study area. In 2011, we conducted a survey of 750 children by selecting 50 from each of the 1 5 clusters. The Helen Keller International's Food-Frequency Questionnaire (HKI-FFQ) modified to the local context was used to assess past week's intake for 28 food-items, including vitamin A-rich foods. The study revealed that plant sources such as amaranth, carrots, etc. and animal sources such as eggs and butter were the major sources of vitamin A in the study population. Consumption of amaranth (2.7 days/week) and carrots (1.7 days/week) was moderate but that of animal foods rich in vitamin A was low to negligible (1.1 day/week for eggs and 0.2 day/week for liver and fish combined). The majority (80%) of the cluster-villages manifested inadequate intake of vitamin A-rich foods, thereby making subclinical vitamin A deficiency a public health problem for the whole area. Faulty diets, improper breastfeeding practices, low coverage of vitamin A supplementation and high prevalence of undernutrition could be related to the observed subclinical deficiency. Dietary diversification by including both plant and animal sources of vitamin A in adequate amounts along with improved breastfeeding, better implementation of mega-dose vitamin A supplementation and minimizing undernutrition may help in lowering subclinical vitamin A deficiency. The HKI-FFQ may be used as a proxy indicator of vitamin A intake/status for identifying pockets at risk of subclinical vitamin A deficiency in resource-constrained settings.
Maternal micronutrient deficiency leads to alteration in the kidney proteome in rat pups.

PubMed

Ahmad, Shadab; Basak, Trayambak; Anand Kumar, K; Bhardwaj, Gourav; Lalitha, A; Yadav, Dilip K; Chandak, Giriraj Ratan; Raghunath, Manchala; Sengupta, Shantanu

2015-09-08

Maternal nutritional deficiency significantly perturbs the offspring's physiology predisposing them to metabolic diseases during adulthood. Vitamin B12 and folate are two such micronutrients, whose deficiency leads to elevated homocysteine levels. We earlier generated B12 and/or folate deficient rat models and using high-throughput proteomic approach, showed that maternal vitamin B12 deficiency modulates carbohydrate and lipid metabolism in the liver of pups through regulation of PPAR signaling pathway. In this study, using similar approach, we identified 26 differentially expressed proteins in the kidney of pups born to mothers fed with vitamin B12 deficient diet while only four proteins were identified in the folate deficient group. Importantly, proteins like calreticulin, cofilin 1 and nucleoside diphosphate kinase B that are involved in the functioning of the kidney were upregulated in B12 deficient group. Our results hint towards a larger effect of vitamin B12 deficiency compared to that of folate presumably due to greater elevation of homocysteine in vitamin B12 deficient group. In view of widespread vitamin B12 and folate deficiency and its association with several diseases like anemia, cardiovascular and renal diseases, our results may have large implications for kidney diseases in populations deficient in vitamin B12 especially in vegetarians and the elderly people.This article is part of a Special Issue entitled: Proteomics in India. Copyright © 2015 Elsevier B.V. All rights reserved.
Cardiac metabolic pathways affected in the mouse model of barth syndrome.

PubMed

Huang, Yan; Powers, Corey; Madala, Satish K; Greis, Kenneth D; Haffey, Wendy D; Towbin, Jeffrey A; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W; Khuchua, Zaza

2015-01-01

Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.
Adult classical homocystinuria requiring parenteral nutrition: Pitfalls and management.

PubMed

Tran, Christel; Bonafé, Luisa; Nuoffer, Jean-Marc; Rieger, Julie; Berger, Mette M

2017-07-25

Homocystinuria due to cystathionine beta synthase (CBS) deficiency presents with a wide clinical spectrum. Treatment by the enteral route aims at reducing homocysteine levels by using vitamin B6, possibly methionine-restricted diet, betaine and/or folate and vitamin B 12 supplementation. Currently no nutritional guidelines exist regarding parenteral nutrition (PN) under acute conditions. Exhaustive literature search was performed, in order to identify the relevant studies describing the pathogenesis and nutritional intervention of adult classical homocystinuria requiring PN. Description of an illustrative case of an adult female with CBS deficiency and intestinal perforation, who required total PN due to contraindication to enteral nutrition. Nutritional management of decompensated classical homocystinuria is complex and currently no recommendation exists regarding PN composition. Amino acid profile and monitoring of total homocysteine concentration are the main tools enabling a precise assessment of the severity of metabolic alterations. In case of contraindication to enteral nutrition, compounded PN will be required, as described in this paper, to ensure adequate low amounts of methionine and others essential amino acids and avoid potentially fatal toxic hypermethioninemia. By reviewing the literature and reporting successful nutritional management of a decompensated CBS deficiency using tailored PN with limited methionine intake and n-3 PUFA addition, we would like to underscore the fact that standard PN solutions are not adapted for CBS deficient critical ill patients: new solutions are required. High methionine levels (>800 μmol/L) being potentially neurotoxic, there is an urgent need to improve our knowledge of acute nutritional therapy. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Visual and brainstem auditory evoked potentials in infants with severe vitamin B12 deficiency.

PubMed

Demir, Nihat; Koç, Ahmet; Abuhandan, Mahmut; Calik, Mustafa; Işcan, Akin

2015-01-01

Vitamin B12 plays an important role in the development of mental, motor, cognitive, and social functions via its role in DNA synthesis and nerve myelination. Its deficiency in infants might cause neuromotor retardation as well as megaloblastic anemia. The objective of this study was to investigate the effects of infantile vitamin B12 deficiency on evoked brain potentials and determine whether improvement could be obtained with vitamin B12 replacement at appropriate dosages. Thirty patients with vitamin B12 deficiency and 30 age-matched healthy controls were included in the study. Hematological parameters, visual evoked potentials, and brainstem auditory evoked potentials tests were performed prior to treatment, 1 week after treatment, and 3 months after treatment. Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) were found to be prolonged in 16 (53.3%) and 15 (50%) patients, respectively. Statistically significant improvements in VEP and BAEP examinations were determined 3 months after treatment. Three months after treatment, VEP and BAEP examinations returned to normal in 81.3% and 53.3% of subjects with prolonged VEPs and BAEPs, respectively. These results demonstrate that vitamin B12 deficiency in infants causes significant impairment in the auditory and visual functioning tests of the brain, such as VEP and BAEP.
Glucose-6-phosphate dehydrogenase deficiency in transfusion medicine: the unknown risks.

PubMed

Francis, R O; Jhang, J S; Pham, H P; Hod, E A; Zimring, J C; Spitalnik, S L

2013-11-01

The hallmark of glucose-6-phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce haemolysis in G6PD-deficient RBCs. Although it is not routine practice to screen healthy blood donors for G6PD deficiency, case reports identified transfusion of G6PD-deficient RBCs as causing haemolysis and other adverse events. In addition, some patient populations may be more at risk for complications associated with transfusions of G6PD-deficient RBCs because they receive RBCs from donors who are more likely to have G6PD deficiency. This review discusses G6PD deficiency, its importance in transfusion medicine, changes in the RBC antioxidant system (of which G6PD is essential) during refrigerated storage and mechanisms of haemolysis. In addition, as yet unanswered questions that could be addressed by translational and clinical studies are identified and discussed. © 2013 International Society of Blood Transfusion.
Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress

PubMed Central

Hewish, M; Martin, S A; Elliott, R; Cunningham, D; Lord, C J; Ashworth, A

2013-01-01

Background: DNA mismatch repair deficiency is present in a significant proportion of a number of solid tumours and is associated with distinct clinical behaviour. Methods: To identify the therapeutic agents that might show selectivity for mismatch repair-deficient tumour cells, we screened a pair of isogenic MLH1-deficient and MLH1-proficient tumour cell lines with a library of clinically used drugs. To test the generality of hits in the screen, selective agents were retested in cells deficient in the MSH2 mismatch repair gene. Results: We identified cytarabine and other related cytosine-based nucleoside analogues as being selectively toxic to MLH1 and MSH2-deficient tumour cells. The selective cytotoxicity we observed was likely caused by increased levels of cellular oxidative stress, as it could be abrogated by antioxidants. Conclusion: We propose that cytarabine-based chemotherapy regimens may represent a tumour-selective treatment strategy for mismatch repair-deficient cancers. PMID:23361057
Peripheral kynurenine-3-monooxygenase deficiency as a potential risk factor for metabolic syndrome in schizophrenia patients.

PubMed

Oxenkrug, Gregory; van der Hart, Marieke; Roeser, Julien; Summergrad, Paul

2017-01-01

Increased predisposition of schizophrenia patients (SP) to development of obesity and insulin resistance suggested common signaling pathway between metabolic syndrome (MetS) and schizophrenia. Deficiency of kynurenine-3-monooxygenase (KMO), enzyme catalyzing formation of 3-hydroxykynurenine (3-HK) from kynurenine (Kyn), a tryptophan (Trp) metabolite, might contribute to development of MetS as suggested by non-expression of KMO genes in human fat tissue and elevated serum concentrations of Kyn and its metabolites, kynurenic (KYNA) and anthranilic (ANA) acids, in diabetic patients and Zucker fatty rats (ZFR). Markers of KMO deficiency: decreased 3-HK and elevated Kyn, KYNA and ANA, were observed in brains and spinal fluids of SP, and in brains and serum of experimental animals with genetically- or pharmacologically-induced KMO deficiency. However, elevated concentrations of ANA and decreased 3-HK were reported in serum of SP without concurrent increase of Kyn and KYNA. Present study aimed to re-assess serum Kyn metabolites (HPLC-MS) in a sub-group of SP with elevated KYNA. We found increased Kyn concentrations (by 30%) and Kyn:Trp ratio (by 20%) in serum of SP with elevated KYNA concentrations (by 40%). Obtained results and our previous data suggest that peripheral KMO deficiency might be manifested by, at least, two different patterns: elevated ANA with decreased 3-HK; and elevated KYNA and KYN. The latter pattern was previously described in type 2 diabetes patients and might underline increased predisposition of SP to development of MetS. Assessment of peripheral KMO deficiency might identify SP predisposed to MetS. Attenuation of the consequences of peripheral KMO deficiency might be a new target for prevention/treatment of obesity and diabetes in SP.
Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus.

PubMed

Tran, Phu V; Kennedy, Bruce C; Lien, Yu-Chin; Simmons, Rebecca A; Georgieff, Michael K

2015-02-15

Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency. Copyright © 2015 the American Physiological Society.
NLRP3 and ASC suppress lupus-like autoimmunity by driving the immunosuppressive effects of TGF-β receptor signalling.

PubMed

Lech, Maciej; Lorenz, Georg; Kulkarni, Onkar P; Grosser, Marian O O; Stigrot, Nora; Darisipudi, Murthy N; Günthner, Roman; Wintergerst, Maximilian W M; Anz, David; Susanti, Heni Eka; Anders, Hans-Joachim

2015-12-01

The NLRP3/ASC inflammasome drives host defence and autoinflammatory disorders by activating caspase-1 to trigger the secretion of mature interleukin (IL)-1β/IL-18, but its potential role in autoimmunity is speculative. We generated and phenotyped Nlrp3-deficient, Asc-deficient, Il-1r-deficient and Il-18-deficient C57BL/6-lpr/lpr mice, the latter being a mild model of spontaneous lupus-like autoimmunity. While lack of IL-1R or IL-18 did not affect the C57BL/6-lpr/lpr phenotype, lack of NLRP3 or ASC triggered massive lymphoproliferation, lung T cell infiltrates and severe proliferative lupus nephritis within 6 months, which were all absent in age-matched C57BL/6-lpr/lpr controls. Lack of NLRP3 or ASC increased dendritic cell and macrophage activation, the expression of numerous proinflammatory mediators, lymphocyte necrosis and the expansion of most T cell and B cell subsets. In contrast, plasma cells and autoantibody production were hardly affected. This unexpected immunosuppressive effect of NLRP3 and ASC may relate to their known role in SMAD2/3 phosphorylation during tumour growth factor (TGF)-β receptor signalling, for example, Nlrp3-deficiency and Asc-deficiency significantly suppressed the expression of numerous TGF-β target genes in C57BL/6-lpr/lpr mice and partially recapitulated the known autoimmune phenotype of Tgf-β1-deficient mice. These data identify a novel non-canonical immunoregulatory function of NLRP3 and ASC in autoimmunity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus

PubMed Central

Kennedy, Bruce C.; Lien, Yu-Chin; Simmons, Rebecca A.; Georgieff, Michael K.

2014-01-01

Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early-life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron-sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency. PMID:25519736
Is vitamin D deficiency a public health concern for low middle income countries? A systematic literature review.

PubMed

Cashman, Kevin D; Sheehy, Tony; O'Neill, Colette M

2018-01-17

Vitamin D deficiency has been receiving increasing attention as a potential public health concern in low and lower-middle income countries (LMICs), of which there are currently 83. We aimed to conduct a comprehensive systematic literature review (SLR) of available data on vitamin D status and prevalence of vitamin D deficiency in all 83 LMICs. We followed the general methodology for SLRs in the area of serum 25-hydroxyvitamin D. Highest priority was placed on identifying relevant population-based studies, followed by cross-sectional studies, and to a lesser extent case-control studies. We adopted the public health convention that a prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D < 25/30 nmol/L) at > 20% in the entire population and/or at-risk population subgroups (infants, children, women of child-bearing age, pregnancy) constitutes a public health issue that may warrant intervention. Our SLR revealed that of the 83 LMICs, 65% (n = 54 countries) had no published studies with vitamin D data suitable for inclusion. Using data from the remaining third, a number of LMICs had evidence of excess burden of vitamin D deficiency in one or more population subgroup(s) using the above convention (Afghanistan, Pakistan, India, Tunisia and Mongolia) as well as possibly other LMICs, albeit with much more limited data. Several LMICs had no evidence of excess burden. Vitamin D deficiency is a public health issue in some, but certainly not all, LMICs. There is a clear need for targeting public health strategies for prevention of vitamin D deficiency in those LMICs with excess burden.
Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Stacey L.; Neuroscience Program, Loyola University Medical Center, Maywood, IL; Department of Anatomy and Cell Biology, University of Illinois Chicago, Chicago, IL

Schwann cells derived from peripheral nerve sheath tumors from individuals with Neurofibromatosis Type 1 (NF1) are deficient for the protein neurofibromin, which contains a GAP-related domain (NF1-GRD). Neurofibromin-deficient Schwann cells have increased Ras activation, increased proliferation in response to certain growth stimuli, increased angiogenic potential, and altered cell morphology. This study examined whether expression of functional NF1-GRD can reverse the transformed phenotype of neurofibromin-deficient Schwann cells from both benign and malignant peripheral nerve sheath tumors. We reconstituted the NF1-GRD using retroviral transduction and examined the effects on cell morphology, growth potential, and angiogenic potential. NF1-GRD reconstitution resulted in morphologic changes,more » a 16-33% reduction in Ras activation, and a 53% decrease in proliferation in neurofibromin-deficient Schwann cells. However, NF1-GRD reconstitution was not sufficient to decrease the in vitro angiogenic potential of the cells. This study demonstrates that reconstitution of the NF1-GRD can at least partially reverse the transformation of human NF1 tumor-derived Schwann cells.« less
77 FR 39425 - Approval and Promulgation of Implementation Plans; Louisiana; Regional Haze State Implementation...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-03

... disapproval because of deficiencies in Louisiana's RH SIP submittal that go beyond the issues addressed in the... submittal includes several deficient provisions. The deficiencies identified in the proposal go beyond those...
Technical Basis for PNNL Beryllium Inventory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Michelle Lynn

2014-07-09

The Department of Energy (DOE) issued Title 10 of the Code of Federal Regulations Part 850, “Chronic Beryllium Disease Prevention Program” (the Beryllium Rule) in 1999 and required full compliance by no later than January 7, 2002. The Beryllium Rule requires the development of a baseline beryllium inventory of the locations of beryllium operations and other locations of potential beryllium contamination at DOE facilities. The baseline beryllium inventory is also required to identify workers exposed or potentially exposed to beryllium at those locations. Prior to DOE issuing 10 CFR 850, Pacific Northwest Nuclear Laboratory (PNNL) had documented the beryllium characterizationmore » and worker exposure potential for multiple facilities in compliance with DOE’s 1997 Notice 440.1, “Interim Chronic Beryllium Disease.” After DOE’s issuance of 10 CFR 850, PNNL developed an implementation plan to be compliant by 2002. In 2014, an internal self-assessment (ITS #E-00748) of PNNL’s Chronic Beryllium Disease Prevention Program (CBDPP) identified several deficiencies. One deficiency is that the technical basis for establishing the baseline beryllium inventory when the Beryllium Rule was implemented was either not documented or not retrievable. In addition, the beryllium inventory itself had not been adequately documented and maintained since PNNL established its own CBDPP, separate from Hanford Site’s program. This document reconstructs PNNL’s baseline beryllium inventory as it would have existed when it achieved compliance with the Beryllium Rule in 2001 and provides the technical basis for the baseline beryllium inventory.« less
CD6 as a potential target for treating multiple sclerosis

PubMed Central

Singer, Nora G.; Whitbred, Joy; Bowen, Michael A.; Lin, Feng

2017-01-01

CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell–driven autoimmune conditions. PMID:28209777
Identifying Protein-Calorie Malnutrition Workshop.

ERIC Educational Resources Information Center

Walker, Susan S.; Barker, Ellen M.

Instructional materials are provided for a workshop to enable participants to assist in identifying patients at risk with protein-calorie malnutrition and in corrrecting this nutritional deficiency. Representative topics are nutrients; protein, mineral, and vitamin sources, functions, and deficiency symptoms; malnutrition; nutritional deficiency…
Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening.

PubMed

Wolf, Barry

2017-04-01

We began screening newborns for biotinidase deficiency disorder in 1984, and now all states in the United States and many countries perform this screening. The purpose of this study was to determine the outcomes of older adolescent and adult individuals with the disorder identified by newborn screening. We located and surveyed, by questionnaire and telephone interviews, 44 individuals with profound biotinidase deficiency identified by newborn screening with a mean age of 23.1 years. All individuals had successfully completed high school, and many were attending or had completed college or graduate school. Compliance in using biotin has been excellent. Several individuals developed a variety of symptoms when they discontinued biotin for days or weeks. These features readily resolved when biotin was resumed. In addition, five treated women had nine uneventful pregnancies and deliveries. Newborn screening for profound biotinidase deficiency and early treatment with biotin result in excellent outcomes for older adolescents and adults with the disorder. In addition, mothers with profound biotinidase deficiency who were treated with biotin had pregnancies with good outcomes. These outcome results indicate that newborn screening for biotinidase deficiency is one of the most successful newborn screening programs.Genet Med 19 4, 396-402.
Mismatch Repair Deficiency Testing in Patients With Colorectal Cancer and Nonadherence to Testing Guidelines in Young Adults.

PubMed

Shaikh, Talha; Handorf, Elizabeth A; Meyer, Joshua E; Hall, Michael J; Esnaola, Nestor F

2018-02-08

Mismatch repair (MMR) deficiency of DNA has been observed in up to 15% of sporadic colorectal cancers (CRCs) and is a characteristic feature of Lynch syndrome, which has a higher incidence in young adults (age, <50 years) with CRC. Mismatch repair deficiency can be due to germline mutations or epigenetic inactivation, affects prognosis and response to systemic therapy, and results in unrepaired repetitive DNA sequences, which increases the risk of multiple malignant tumors. To evaluate the utilization of MMR deficiency testing in adults with CRC and analyze nonadherence to long-standing testing guidelines in younger adults using a contemporary national data set to help identify potential risk factors for nonadherence to newly implemented universal testing guidelines. Adult (age, <30 to ≥70 years) and, of these, younger adult (<30 to 49 years) patients with invasive colorectal adenocarcinoma diagnosed between 2010 and 2012 and known MMR deficiency testing status were identified using the National Cancer Database. The study was conducted from March 16, 2016, to March 1, 2017. Patient sociodemographic, facility, tumor, and treatment characteristics. The primary outcome of interest was receipt of MMR deficiency testing. Multivariable logistic regression was used to identify independent predictors of testing in adult and/or young adult patients. A total of 152 993 adults with CRC were included in the study (78 579 [51.4%] men; mean [SD] age, 66.9 [13.9] years). Of these patients, only 43 143 (28.2%) underwent MMR deficiency testing; the proportion of patients tested increased between 2010 and 2012 (22.3% vs 33.1%; P<.001). Among 17 218 younger adult patients with CRC, only 7422 (43.1%) underwent MMR deficiency testing; the proportion tested increased between 2010 and 2012 (36.1% vs 48.0%; P < .001). Irrespective of age, higher educational level (OR, 1.38; 95% CI, 1.15-1.66), later diagnosis year (OR, 1.81; 95% CI, 1.65-1.98), early stage disease (OR, 1.24; 95% CI, 1.18-1.30), and number of regional lymph nodes examined (≥12) (OR, 1.44; 95% CI, 1.34-1.55) were independently associated with MMR deficiency testing, whereas older age (OR, 0.31; 95% CI, 0.26-0.37); Medicare (OR, 0.89; 95% CI, 0.84-0.95), Medicaid (OR, 0.83; 95% CI, 0.73-0.93), or uninsured (OR, 0.78; 95% CI, 0.66-0.92) status; nonacademic vs academic/research facility type (OR, 0.44; 95% CI, 0.34-0.56); rectosigmoid or rectal tumor location (OR, 0.76; 95% CI, 0.68-0.86); unknown grade (OR, 0.61; 95% CI, 0.53-0.69); and nonreceipt of definitive surgery (OR, 0.33; 95% CI, 0.30-0.37) were associated with underuse of MMR deficiency testing. Despite recent endorsement of universal use of MMR deficiency testing in patients with CRC and well-established guidelines aimed at high-risk populations, overall utilization of testing is poor and significant underuse of testing among young adults persists. Interventions tailored to groups at risk for nonadherence to guidelines may be warranted in the current era of universal testing.
A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency.

PubMed

O'Reilly, Linda P; Long, Olivia S; Cobanoglu, Murat C; Benson, Joshua A; Luke, Cliff J; Miedel, Mark T; Hale, Pamela; Perlmutter, David H; Bahar, Ivet; Silverman, Gary A; Pak, Stephen C

2014-10-01

α1-Antitrypsin deficiency (ATD) is a common genetic disorder that can lead to end-stage liver and lung disease. Although liver transplantation remains the only therapy currently available, manipulation of the proteostasis network (PN) by small molecule therapeutics offers great promise. To accelerate the drug-discovery process for this disease, we first developed a semi-automated high-throughput/content-genome-wide RNAi screen to identify PN modifiers affecting the accumulation of the α1-antitrypsin Z mutant (ATZ) in a Caenorhabditis elegans model of ATD. We identified 104 PN modifiers, and these genes were used in a computational strategy to identify human ortholog-ligand pairs. Based on rigorous selection criteria, we identified four FDA-approved drugs directed against four different PN targets that decreased the accumulation of ATZ in C. elegans. We also tested one of the compounds in a mammalian cell line with similar results. This methodology also proved useful in confirming drug targets in vivo, and predicting the success of combination therapy. We propose that small animal models of genetic disorders combined with genome-wide RNAi screening and computational methods can be used to rapidly, economically and strategically prime the preclinical discovery pipeline for rare and neglected diseases with limited therapeutic options. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development.

PubMed

Beutler, Ernest; Duparc, Stephan

2007-10-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is relatively common in populations exposed to malaria. This deficiency appears to provide some protection from this infection, but it can also cause hemolysis after administration of some antimalarial drugs, especially primaquine. The risk of drug-induced G6PD deficiency-related hemolysis depends on a number of factors including the G6PD variant, the drug and drug dosage schedule, patient status, and disease factors. Although a great deal is known about the molecular biology of G6PD, determining the potential for drug-induced hemolysis in the clinical setting is still challenging. This report discusses the potential strategies for assessing drug-induced G6PD deficiency-related hemolytic risk preclinically and in early clinical trials. Additionally, the issues important for conducting larger clinical trials in populations in which G6PD deficiency is prevalent are examined, with a particular focus on antimalarial drug development.
Strategic Assessment of Trauma Care Capacity in Ghana.

PubMed

Stewart, Barclay T; Quansah, Robert; Gyedu, Adam; Ankomah, James; Donkor, Peter; Mock, Charles

2015-10-01

This study aimed to assess availability of trauma care technology in Ghana. In addition, factors contributing to deficiencies were evaluated. By doing so, potential solutions to inefficient aspects of health systems management and maladapted technology for trauma care in low- and middle-income countries (LMICs) could be identified. Thirty-two items were selected from the World Health Organization's Guidelines for Essential Trauma Care. Direct inspection and structured interviews with administrative, clinical, and biomedical engineering staff were used to assess the challenges and successes of item availability at 40 purposively sampled district, regional, and tertiary hospitals. Hospital assessments demonstrated marked deficiencies. Some of these were low cost, such as basic airway supplies, chest tubes, and cervical collars. Item non-availability resulted from several contributing factors, namely equipment absence, lack of training, frequent stock-outs, and technology breakage. A number of root causes for these factors were identified, including ineffective healthcare financing by way of untimely national insurance reimbursements, procurement and stock-management practices, and critical gaps in local biomedical engineering and trauma care training. Nonetheless, local examples of successfully overcoming deficiencies were identified (e.g., public-private partnering, ensuring company engineers trained technicians on-the-job during technology installation or servicing). While availability of several low-cost items could be better supplied by improvements in stock-management and procurement policies, there is a critical need for redress of the national insurance reimbursement system and trauma care training of district hospital staff. Further, developing local service and technical support capabilities is more and more pressing as technology plays an increasingly important role in LMIC healthcare systems.
Analysis of physiological and miRNA responses to Pi deficiency in alfalfa (Medicago sativa L.).

PubMed

Li, Zhenyi; Xu, Hongyu; Li, Yue; Wan, Xiufu; Ma, Zhao; Cao, Jing; Li, Zhensong; He, Feng; Wang, Yufei; Wan, Liqiang; Tong, Zongyong; Li, Xianglin

2018-03-01

The induction of miR399 and miR398 and the inhibition of miR156, miR159, miR160, miR171, miR2111, and miR2643 were observed under Pi deficiency in alfalfa. The miRNA-mediated genes involved in basic metabolic process, root and shoot development, stress response and Pi uptake. Inorganic phosphate (Pi) deficiency is known to be a limiting factor in plant development and growth. However, the underlying miRNAs associated with the Pi deficiency-responsive mechanism in alfalfa are unclear. To elucidate the molecular mechanism at the miRNA level, we constructed four small RNA (sRNA) libraries from the roots and shoots of alfalfa grown under normal or Pi-deficient conditions. In the present study, alfalfa plants showed reductions in biomass, photosynthesis, and Pi content and increases in their root-to-shoot ratio and citric, malic, and succinic acid contents under Pi limitation. Sequencing results identified 47 and 44 differentially expressed miRNAs in the roots and shoots, respectively. Furthermore, 909 potential target genes were predicted, and some targets were validated by RLM-RACE assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed prominent enrichment in signal transducer activity, binding and basic metabolic pathways for carbohydrates, fatty acids and amino acids; cellular response to hormone stimulus and response to auxin pathways were also enriched. qPCR results verified that the differentially expressed miRNA profile was consistent with sequencing results, and putative target genes exhibited opposite expression patterns. In this study, the miRNAs associated with the response to Pi limitation in alfalfa were identified. In addition, there was an enrichment of miRNA-targeted genes involved in biological regulatory processes such as basic metabolic pathways, root and shoot development, stress response, Pi transportation and citric acid secretion.
Prenatal exposure of a girl with autism spectrum disorder to 'horsetail' (Equisetum arvense) herbal remedy and alcohol: a case report

PubMed Central

2011-01-01

Introduction Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences are thought to play a causal role. In humans, throughout embryonic and fetal life, brain development is exquisitely susceptible to injury caused by exposure to toxic chemicals present in the environment. Although the use of herbal supplements during pregnancy is relatively common, little information is available on their association with fetal neurodevelopment. This is, to the best of our knowledge, the first report in the literature to associate a new plausible mechanism of neurodevelopmental toxicity with a case of autism spectrum disorder through a vitamin deficiency potentiated by concomitant use of herbal supplements and ethanol exposure. Case presentation We describe the pediatric environmental history of a three-year-old Caucasian girl with an autism spectrum disorder. We utilized her pediatric environmental history to evaluate constitutional, genetic, and environmental factors pertinent to manifestation of neurodevelopment disorders. Both parents reported prenatal exposure to several risk factors of interest. A year prior to conception the mother began a weight loss diet and ingested 1200 mg/day of 'horsetail' (Equisetum arvense) herbal remedies containing thiaminase, an enzyme that with long-term use can lead to vitamin deficiency. The mother reported a significant weight loss during the pregnancy and a deficiency of B-complex vitamins. Thiamine (vitamin B1) deficiency could have been potentiated by the horsetail's thiaminase activity and ethanol exposure during pregnancy. No other risk factors were identified. Conclusions A detailed and careful pediatric environmental history, which includes daily intake, herbal remedies and ethanol exposure, should be obtained from all patients with autism spectrum disorder. Maternal consumption of ethanol and of herbal supplements with suspected or potential toxicity should be avoided during pregnancy. The prospective parents should perform preconception planning before pregnancy. PMID:21453474

Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein

PubMed Central

Park, Daeho; Han, Claudia; Elliott, Michael R.; Kinchen, Jason M.; Trampont, Paul C.; Das, Soumita; Collins, Sheila; Lysiak, Jeffrey J.; Hoehn, Kyle L.; Ravichandran, Kodi S.

2012-01-01

Rapid and efficient removal of apoptotic cells by phagocytes plays a key role during development, tissue homeostasis, and in controlling immune responses1–5. An important feature of efficient clearance is the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the increased load of corpse-derived cellular material6–9. However, factors that influence sustained phagocytic capacity or how they in turn influence continued clearance by phagocytes are not known. Here we identify that the ability of a phagocyte to control its mitochondrial membrane potential is a critical factor in the capacity of a phagocyte to engulf apoptotic cells. Changing the phagocyte mitochondrial membrane potential (genetically or pharmacologically) significantly affected phagocytosis, with lower potential enhancing engulfment and higher membrane potential inhibiting uptake. We then identified that Ucp2, a mitochondrial membrane protein that acts to lower the mitochondrial membrane potential10–12, is upregulated in phagocytes engulfing apoptotic cells (but not synthetic targets, bacteria, or yeast). Loss of Ucp2 limited the capacity of phagocytes to continually ingest apoptotic cells, while overexpression of Ucp2 increased the capacity for engulfment and the ability to engulf multiple apoptotic cells. Mutational and pharmacological inhibition of Ucp2 uncoupling activity reversed the positive effect of Ucp2 on engulfment capacity, suggesting a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-deficient mice13, 14 were impaired in their capacity to engulf apoptotic cells in vitro, and Ucp2-deficient mice displayed profound in vivo defects in clearing dying cells in the thymus and the testes. Collectively, these data suggest that phagocytes alter the mitochondrial membrane potential during engulfment to regulate uptake of sequential apoptotic cells, and that Ucp2 is a key molecular determinant of this step in vivo. Since Ucp2 function has also been linked to metabolic diseases and atherosclerosis14–16, these data identifying a new role for Ucp2 in regulating apoptotic cell clearance may provide additional insights toward understanding the complex etiology and pathogenesis of these diseases. PMID:21857682
Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus.

PubMed

Tran, Phu V; Kennedy, Bruce C; Pisansky, Marc T; Won, Kyoung-Jae; Gewirtz, Jonathan C; Simmons, Rebecca A; Georgieff, Michael K

2016-03-01

Early-life iron deficiency is a common nutrient deficiency worldwide. Maternal iron deficiency increases the risk of schizophrenia and autism in the offspring. Postnatal iron deficiency in young children results in cognitive and socioemotional abnormalities in adulthood despite iron treatment. The rat model of diet-induced fetal-neonatal iron deficiency recapitulates the observed neurobehavioral deficits. We sought to establish molecular underpinnings for the persistent psychopathologic effects of early-life iron deficiency by determining whether it permanently reprograms the hippocampal transcriptome. We also assessed the effects of maternal dietary choline supplementation on the offspring's hippocampal transcriptome to identify pathways through which choline mitigates the emergence of long-term cognitive deficits. Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (4 g Fe/kg) from gestational day (G) 2 through postnatal day (PND) 7 and an iron-sufficient (IS) diet (200 g Fe/kg) thereafter. Control pups were provided IS diet throughout. Choline (5 g/kg) was given to half the pregnant dams in each group from G11 to G18. PND65 hippocampal transcriptomes were assayed by next generation sequencing (NGS) and analyzed with the use of knowledge-based Ingenuity Pathway Analysis. Real-time polymerase chain reaction was performed to validate a subset of altered genes. Formerly ID rats had altered hippocampal expression of 619 from >10,000 gene loci sequenced by NGS, many of which map onto molecular networks implicated in psychological disorders, including anxiety, autism, and schizophrenia. There were significant interactions between iron status and prenatal choline treatment in influencing gene expression. Choline supplementation reduced the effects of iron deficiency, including those on gene networks associated with autism and schizophrenia. Fetal-neonatal iron deficiency reprograms molecular networks associated with the pathogenesis of neurologic and psychological disorders in adult rats. The positive response to prenatal choline represents a potential adjunctive therapeutic supplement to the high-risk group. © 2016 American Society for Nutrition.
Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies.

PubMed

Davidoff, Candice; Neitz, Maureen; Neitz, Jay

2016-09-01

The genetics underlying inherited color vision deficiencies is well understood: causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes. This study evaluated the potential of opsin gene analyses for use in clinical diagnosis of color vision defects. We tested 1872 human subjects using direct sequencing of opsin genes and a novel genetic assay that characterizes single nucleotide polymorphisms (SNPs) using the MassArray system. Of the subjects, 1074 also were given standard psychophysical color vision tests for a direct comparison with current clinical methods. Protan and deutan deficiencies were classified correctly in all subjects identified by MassArray as having red-green defects. Estimates of defect severity based on SNPs that control photopigment spectral tuning correlated with estimates derived from Nagel anomaloscopy. The MassArray assay provides genetic information that can be useful in the diagnosis of inherited color vision deficiency including presence versus absence, type, and severity, and it provides information to patients about the underlying pathobiology of their disease. The MassArray assay provides a method that directly analyzes the molecular substrates of color vision that could be used in combination with, or as an alternative to current clinical diagnosis of color defects.
Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years

PubMed Central

Congdon, Eliza L.; Westerlund, Alissa; Algarin, Cecilia R.; Peirano, Patricio D.; Gregas, Matthew; Lozoff, Betsy; Nelson, Charles A.

2012-01-01

Objective To determine the long-term effects of iron deficiency on the neural correlates of recognition memory. Study design Non-anemic control participants (n=93) and 116 otherwise healthy formerly iron-deficient anemic (FIDA) Chilean children were selected from a larger longitudinal study. Participants were identified at 6, 12, or 18 months as iron-deficient anemic or non-anemic and subsequently received oral iron treatment. This follow-up was conducted when participants were 10 years old. Behavioral measures and event-related potentials from 28 scalp electrodes were measured during an old/new word recognition memory task. Results The new/old effect of the FN400 amplitude, where new words are associated with greater amplitude than old words, was present within the control group only. The control group also showed faster FN400 latency than the FIDA group and larger mean amplitude for the P300 component. Conclusions Although overall behavioral performance is comparable between groups, the results show that group differences in cognitive function have not been resolved ten years after iron treatment. Long-lasting changes in myelination and energy metabolism, perhaps especially in the hippocampus, may account for these long-term effects on an important aspect of human cognitive development. PMID:22244466
Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies

PubMed Central

Davidoff, Candice; Neitz, Maureen; Neitz, Jay

2016-01-01

Purpose The genetics underlying inherited color vision deficiencies is well understood: causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes. This study evaluated the potential of opsin gene analyses for use in clinical diagnosis of color vision defects. Methods We tested 1872 human subjects using direct sequencing of opsin genes and a novel genetic assay that characterizes single nucleotide polymorphisms (SNPs) using the MassArray system. Of the subjects, 1074 also were given standard psychophysical color vision tests for a direct comparison with current clinical methods. Results Protan and deutan deficiencies were classified correctly in all subjects identified by MassArray as having red–green defects. Estimates of defect severity based on SNPs that control photopigment spectral tuning correlated with estimates derived from Nagel anomaloscopy. Conclusions The MassArray assay provides genetic information that can be useful in the diagnosis of inherited color vision deficiency including presence versus absence, type, and severity, and it provides information to patients about the underlying pathobiology of their disease. Translational Relevance The MassArray assay provides a method that directly analyzes the molecular substrates of color vision that could be used in combination with, or as an alternative to current clinical diagnosis of color defects. PMID:27622081
A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency

NASA Astrophysics Data System (ADS)

Tharkeshwar, Arun Kumar; Trekker, Jesse; Vermeire, Wendy; Pauwels, Jarne; Sannerud, Ragna; Priestman, David A.; Te Vruchte, Danielle; Vints, Katlijn; Baatsen, Pieter; Decuypere, Jean-Paul; Lu, Huiqi; Martin, Shaun; Vangheluwe, Peter; Swinnen, Johannes V.; Lagae, Liesbet; Impens, Francis; Platt, Frances M.; Gevaert, Kris; Annaert, Wim

2017-01-01

Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions.
lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1.

PubMed

Liu, Xiaowen; Gan, Boyi

2016-12-16

Biguanides, including metformin (widely used in diabetes treatment) and phenformin, are AMP-activated protein kinase (AMPK) activators and potential drugs for cancer treatment. A more in-depth understanding of how cancer cells adapt to biguanide treatment may provide important therapeutic implications to achieve more effective and rational cancer therapies. NBR2 is a glucose starvation-induced long non-coding RNA (lncRNA) that interacts with AMPK and regulates AMPK activity upon glucose starvation. Here we show that phenformin treatment induces NBR2 expression, and NBR2 deficiency sensitizes cancer cells to phenformin-induced cell death. Surprisingly, unlike glucose starvation, phenformin does not induce NBR2 interaction with AMPK, and correspondingly, NBR2 deficiency does not affect phenformin-induced AMPK activation. We further reveal that NBR2 depletion attenuates phenformin-induced glucose transporter GLUT1 expression and glucose uptake. GLUT1 deficiency sensitizes cancer cells to phenformin-induced cell death, whereas GLUT1 restoration in NBR2 deficient cells rescues the increased cell death upon phenformin treatment. Together, the results of our study reveal that NBR2-GLUT1 axis may serve as an adaptive response in cancer cells to survive in response to phenformin treatment, and identify a novel mechanism coupling lncRNA to biguanide-mediated biology.
lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1

PubMed Central

Liu, Xiaowen; Gan, Boyi

2016-01-01

ABSTRACT Biguanides, including metformin (widely used in diabetes treatment) and phenformin, are AMP-activated protein kinase (AMPK) activators and potential drugs for cancer treatment. A more in-depth understanding of how cancer cells adapt to biguanide treatment may provide important therapeutic implications to achieve more effective and rational cancer therapies. NBR2 is a glucose starvation-induced long non-coding RNA (lncRNA) that interacts with AMPK and regulates AMPK activity upon glucose starvation. Here we show that phenformin treatment induces NBR2 expression, and NBR2 deficiency sensitizes cancer cells to phenformin-induced cell death. Surprisingly, unlike glucose starvation, phenformin does not induce NBR2 interaction with AMPK, and correspondingly, NBR2 deficiency does not affect phenformin-induced AMPK activation. We further reveal that NBR2 depletion attenuates phenformin-induced glucose transporter GLUT1 expression and glucose uptake. GLUT1 deficiency sensitizes cancer cells to phenformin-induced cell death, whereas GLUT1 restoration in NBR2 deficient cells rescues the increased cell death upon phenformin treatment. Together, the results of our study reveal that NBR2-GLUT1 axis may serve as an adaptive response in cancer cells to survive in response to phenformin treatment, and identify a novel mechanism coupling lncRNA to biguanide-mediated biology. PMID:27792451
Sudden Deaths Among Oil and Gas Extraction Workers Resulting from Oxygen Deficiency and Inhalation of Hydrocarbon Gases and Vapors - United States, January 2010-March 2015.

PubMed

Harrison, Robert J; Retzer, Kyla; Kosnett, Michael J; Hodgson, Michael; Jordan, Todd; Ridl, Sophia; Kiefer, Max

2016-01-15

In 2013, an occupational medicine physician from the University of California, San Francisco, contacted CDC's National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA) about two oil and gas extraction worker deaths in the western United States. The suspected cause of these deaths was exposure to hydrocarbon gases and vapors (HGVs) and oxygen (O2)-deficient atmospheres after opening the hatches of hydrocarbon storage tanks. The physician and experts from NIOSH and OSHA reviewed available fatality reports from January 2010 to March 2015, and identified seven additional deaths with similar characteristics (nine total deaths). Recommendations were made to industry and regulators regarding the hazards associated with opening hatches of tanks, and controls to reduce or eliminate the potential for HGV exposure were proposed. Health care professionals who treat or evaluate oil and gas workers need to be aware that workers might report symptoms of exposure to high concentrations of HGVs and possible O2 deficiency; employers and workers need to be aware of this hazard and know how to limit exposure. Medical examiners investigating the death of oil and gas workers who open tank hatches should consider the contribution of O2 deficiency and HGV exposure.
Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).

PubMed

Buchanan, Daniel D; Rosty, Christophe; Clendenning, Mark; Spurdle, Amanda B; Win, Aung Ko

2014-01-01

Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives.
The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.

PubMed

Vendetti, Frank P; Lau, Alan; Schamus, Sandra; Conrads, Thomas P; O'Connor, Mark J; Bakkenist, Christopher J

2015-12-29

ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.
Causes of severe visual impairment and blindness in students in schools for the blind in Northwest Ethiopia.

PubMed

Asferaw, Mulusew; Woodruff, Geoffrey; Gilbert, Clare

2017-01-01

To determine the causes of severe visual impairment and blindness (SVI/BL) among students in schools for the blind in Northwest Ethiopia and to identify preventable and treatable causes. Students attending nine schools for the blind in Northwest Ethiopia were examined and causes assigned using the standard WHO record form for children with blindness and low vision in May and June 2015. 383 students were examined, 357 (93%) of whom were severely visually impaired or blind (<6/60 in their better eye). 253 (70.9%) were aged 16 years or above and 228 (63.9%) were males. 100 students aged <16 years were blind and four were SVI, total 104. The major anatomical site of visual loss among those 0-15 years was cornea/phthisis (47.1%), usually due to measles and vitamin A deficiency, followed by whole globe (22.1%), lens (9.6%) and uvea (8.7%). Among students aged 16 years and above, corneal/phthisis (76.3%) was the major anatomical cause, followed by lens (6.3%), whole globe (4.7%), uvea (3.6%) and optic nerve (3.2%). The leading underlying aetiology among students aged <16 years was childhood factors (39.4%) (13.5% measles, 10.6% vitamin A deficiency), followed by unknown aetiology (54.8%), perinatal (2.9%) and hereditary factors (2.9%). In the older group, childhood factors (72.3%) (25% measles, 15% vitamin A deficiency) were major causes, followed by unknown aetiology (24.1%), perinatal (2.4%) and hereditary factors (0.8%). Over 80% of the causes were avoidable with majority being potentially preventable (65%). Corneal blindness, mainly as the result of measles and vitamin A deficiency, is still a public health problem in Northwest Ethiopia, and this has not changed as observed in other low-income countries. More than three-fourth of causes of SVI/BL in students in schools for the blind are potentially avoidable, with measles/vitamin A deficiency and cataract being the leading causes.
Inhibition of GSK-3β Rescues the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice

PubMed Central

Loiselle, Alayna E.; Lloyd, Shane A. J.; Paul, Emmanuel M.; Lewis, Gregory S.; Donahue, Henry J.

2013-01-01

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair. PMID:24260576
Segregation for chlorophyll deficiencies and other phenodeviants in the x1 and x2 generations of irradiated jack pine

Treesearch

Thomas D. Rudolph

1966-01-01

Readily identifiable phenotypes, such as cotyledonary chlorophyll deficiencies, whose genetic basis can be established, would be highly useful in forest genetics research as genetic markers. In the genus Pinus mutants with severe deficiencies, such as albinos, will die shortly after seed germination while those with less severe deficiencies will not...
How prevalent is vitamin B(12) deficiency among vegetarians?

PubMed

Pawlak, Roman; Parrott, Scott James; Raj, Sudha; Cullum-Dugan, Diana; Lucus, Debbie

2013-02-01

Vegetarians are at risk for vitamin B(12) (B12) deficiency due to suboptimal intake. The goal of the present literature review was to assess the rate of B12 depletion and deficiency among vegetarians and vegans. Using a PubMed search to identify relevant publications, 18 articles were found that reported B12 deficiency rates from studies that identified deficiency by measuring methylmalonic acid, holo-transcobalamin II, or both. The deficiency rates reported for specific populations were as follows: 62% among pregnant women, between 25% and almost 86% among children, 21-41% among adolescents, and 11-90% among the elderly. Higher rates of deficiency were reported among vegans compared with vegetarians and among individuals who had adhered to a vegetarian diet since birth compared with those who had adopted such a diet later in life. The main finding of this review is that vegetarians develop B12 depletion or deficiency regardless of demographic characteristics, place of residency, age, or type of vegetarian diet. Vegetarians should thus take preventive measures to ensure adequate intake of this vitamin, including regular consumption of supplements containing B12. © 2012 International Life Sciences Institute.
High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans

PubMed Central

Coussens, Anna K.; Naude, Celeste E.; Goliath, Rene; Chaplin, George; Wilkinson, Robert J.; Jablonski, Nina G.

2015-01-01

Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity. PMID:26080414
High-dose vitamin D3 reduces deficiency caused by low UVB exposure and limits HIV-1 replication in urban Southern Africans

NASA Astrophysics Data System (ADS)

Coussens, Anna K.; Naude, Celeste E.; Goliath, Rene; Chaplin, George; Wilkinson, Robert J.; Jablonski, Nina G.

2015-06-01

Cape Town, South Africa, has a seasonal pattern of UVB radiation and a predominantly dark-skinned urban population who suffer high HIV-1 prevalence. This coexistent environmental and phenotypic scenario puts residents at risk for vitamin D deficiency, which may potentiate HIV-1 disease progression. We conducted a longitudinal study in two ethnically distinct groups of healthy young adults in Cape Town, supplemented with vitamin D3 in winter, to determine whether vitamin D status modifies the response to HIV-1 infection and to identify the major determinants of vitamin D status (UVB exposure, diet, pigmentation, and genetics). Vitamin D deficiency was observed in the majority of subjects in winter and in a proportion of individuals in summer, was highly correlated with UVB exposure, and was associated with greater HIV-1 replication in peripheral blood cells. High-dosage oral vitamin D3 supplementation attenuated HIV-1 replication, increased circulating leukocytes, and reversed winter-associated anemia. Vitamin D3 therefore presents as a low-cost supplementation to improve HIV-associated immunity.
Estrogen Inhibits Dlk1/FA1 Production: A Potential Mechanism for Estrogen Effects on Bone Turnover

PubMed Central

Abdallah, B. M.; Bay-Jensen, A.; Srinivasan, B.; Tabassi, N. C.; Garnero, P.; Delaissé, J.; Khosla, S.; Kassem, M.

2011-01-01

We have recently identified Dlk1/FA1 (Delta-like 1/FA1) as a novel regulator of bone mass that functions to mediate bone loss, under estrogen deficiency, in mice. In this report, we investigated the effects of estrogen (E)-deficiency and E replacement on serum (s) levels of Dlk1/FA1 (s-Dlk1FA1) and its correlation with bone turnover markers. s-Dlk1/FA1 and bone turnover markers (s-CTx and s-osteocalcin), were measured in two cohorts: a group of pre- and postmenopausal women (n=100) and a group of postmenopausal women, where half had received estrogen replacement therapy (ERT) (n=166). s-Dlk1/FA1, and s-CTX were elevated in postmenopausal E-deficient compared to premenopausal E-replete women (both; P<0.001). s-Dlk1/FA1 was correlated with s-CTX (r=0.30, P<0.01). ERT, in postmenopausal women, decreased s-Dlk1/FA1, as well as s-CTX and s-osteoclacin (all; P<0.0001). Changes in s-Dlk1 were significantly correlated with those observed in s-CTx (r=0.18, P<0.05) and s-osteocalcin (r=0.28, P<0.001). In conclusion, s-Dlk1/FA1 is influenced by E-deficiency and is correlated with bone turnover. Increased levels of s-Dlk1/FA1 in post-menopausal women may be a mechanism mediating the effects estrogen deficiency on bone turnover. PMID:21681814
Vitamin and mineral status: effects on physical performance.

PubMed

Lukaski, Henry C

2004-01-01

Public health recommendations encourage the selection of a balanced diet and increasing physical activity to foster health and well-being. Whereas the adverse effects of restricted intakes of protein, fat, and carbohydrate on physical performance are well known, there is limited information about the impact of low intakes of vitamins and minerals on the exercise capacity and performance of humans. Physically active people generally consume amounts of vitamins and minerals consistent with the recommendations for the general public. However, when intakes are less than recommendations, some noticeable functional impairments occur. Acute or short-term marginal deficiencies, identified by blood biochemical measures of vitamin B status, had no impacts on performance measures. Severe deprivation of folate and vitamin B12 result in anemia and reduce endurance work performance. Evidence of vitamin A and E deficiencies in athletic individuals is lacking apparently because body storage is appreciable. In contrast to vitamins, marginal mineral deficiencies impair performance. Iron deficiency, with or without anemia, impairs muscle function and limits work capacity. Magnesium deprivation increases oxygen requirements to complete submaximal exercise and reduces endurance performance. Use of vitamin and mineral supplements does not improve measures of performance in people consuming adequate diets. Young girls and individuals participating in activities with weight classifications or aesthetic components are prone to nutrient deficiencies because they restrict food intake and specific micronutrient-rich foods. This information will be useful to professionals who counsel physically active people and scientific groups who make dietary recommendations to improve health and optimize genetic potential.
High-throughput drug screen identifies chelerythrine as a selective inducer of death in a TSC2-null setting.

PubMed

Medvetz, Doug; Sun, Yang; Li, Chenggang; Khabibullin, Damir; Balan, Murugabaskar; Parkhitko, Andrey; Priolo, Carmen; Asara, John M; Pal, Soumitro; Yu, Jane; Henske, Elizabeth P

2015-01-01

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome associated with tumors of the brain, heart, kidney, and lung. The TSC protein complex inhibits the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Inhibitors of mTORC1, including rapamycin, induce a cytostatic response in TSC tumors, resulting in temporary disease stabilization and prompt regrowth when treatment is stopped. The lack of TSC-specific cytotoxic therapies represents an important unmet clinical need. Using a high-throughput chemical screen in TSC2-deficient, patient-derived cells, we identified a series of molecules antagonized by rapamycin and therefore selective for cells with mTORC1 hyperactivity. In particular, the cell-permeable alkaloid chelerythrine induced reactive oxygen species (ROS) and depleted glutathione (GSH) selectively in TSC2-null cells based on metabolic profiling. N-acetylcysteine or GSH cotreatment protected TSC2-null cells from chelerythrine's effects, indicating that chelerythrine-induced cell death is ROS dependent. Induction of heme-oxygenase-1 (HMOX1/HO-1) with hemin also blocked chelerythrine-induced cell death. In vivo, chelerythrine inhibited the growth of TSC2-null xenograft tumors with no evidence of systemic toxicity with daily treatment over an extended period of time. This study reports the results of a bioactive compound screen and the identification of a potential lead candidate that acts via a novel oxidative stress-dependent mechanism to selectively induce necroptosis in TSC2-deficient tumors. This study demonstrates that TSC2-deficient tumor cells are hypersensitive to oxidative stress-dependent cell death, and provide critical proof of concept that TSC2-deficient cells can be therapeutically targeted without the use of a rapalog to induce a cell death response. ©2014 American Association for Cancer Research.

Enhanced Venous Thrombus Resolution in Plasminogen Activator Inhibitor Type-2 Deficient Mice

PubMed Central

Siefert, Suzanne A; Chabasse, Christine; Mukhopadhyay, Subhradip; Hoofnagle, Mark H; Strickland, Dudley K; Sarkar, Rajabrata; Antalis, Toni M

2014-01-01

Background The resolution of deep vein thrombosis (DVT) requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. PAI-2 is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA. Objective To investigate the role of PAI-2 in venous thrombus formation and resolution. Methods Venous thrombus resolution was compared in wild type C57BL/6, PAI-2 -/- and PAI-1 -/- mice using the stasis model of DVT. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA, and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration. Results We found that absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2 -/- mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2 deficient thrombi had increased levels of the neutrophil chemoattractant, CXCL2, which was associated with early enhanced neutrophil recruitment. Conclusions These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution. PMID:25041188
Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice.

PubMed

Siefert, S A; Chabasse, C; Mukhopadhyay, S; Hoofnagle, M H; Strickland, D K; Sarkar, R; Antalis, T M

2014-10-01

The resolution of deep vein thrombosis requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA. To investigate the role of PAI-2 in venous thrombus formation and resolution. Venous thrombus resolution was compared in wild-type C57BL/6, PAI-2(-/-) , and PAI-1(-/-) mice using the stasis model of deep vein thrombosis. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration. We found that the absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2(-/-) mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2-deficient thrombi had increased levels of the neutrophil chemoattractant CXCL2, which was associated with early enhanced neutrophil recruitment. These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution. © 2014 International Society on Thrombosis and Haemostasis.
Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency.

PubMed

Smith, Amanda; McBride, Skye; Marcadier, Julien L; Michaud, Jean; Al-Dirbashi, Osama Y; Schwartzentruber, Jeremy; Beaulieu, Chandree L; Katz, Sherri L; Majewski, Jacek; Bulman, Dennis E; Geraghty, Michael T; Harper, Mary-Ellen; Chakraborty, Pranesh; Lines, Matthew A

2016-01-01

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient's organic acids confirmed the D- and L-2-hydroxyglutaric aciduria typical of DL-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders. One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.
Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children.

PubMed

Léger, Juliane; Mohamed, Damir; Dos Santos, Sophie; Ben Azoun, Myriam; Zénaty, Delphine; Simon, Dominique; Paulsen, Anne; Martinerie, Laetitia; Chevenne, Didier; Alberti, Corinne; Carel, Jean-Claude; Guilmin-Crepon, Sophie

2017-09-01

Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety. To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels. This observational cohort study included all patients ( n = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data. Over a median of 4.0 (2-5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose ( P < 0.01), etiological group ( P < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect. These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions. © 2017 European Society of Endocrinology.
Addressing Perceived Skill Deficiencies in Student Affairs Graduate Preparation Programs

ERIC Educational Resources Information Center

Cooper, Jay; Mitchell, Donald, Jr.; Eckerle, Kayle; Martin, Kyle

2016-01-01

This article explores existing literature on perceived skill deficiencies among entry-level student affairs practitioners. Through a review of recent literature, seven perceived skill deficiencies were identified, including budgeting and financial management, strategic planning, research and assessment, legal knowledge and standards, supervision,…
Data on xylem sap proteins from Mn- and Fe-deficient tomato plants obtained using shotgun proteomics.

PubMed

Ceballos-Laita, Laura; Gutierrez-Carbonell, Elain; Takahashi, Daisuke; Abadía, Anunciación; Uemura, Matsuo; Abadía, Javier; López-Millán, Ana Flor

2018-04-01

This article contains consolidated proteomic data obtained from xylem sap collected from tomato plants grown in Fe- and Mn-sufficient control, as well as Fe-deficient and Mn-deficient conditions. Data presented here cover proteins identified and quantified by shotgun proteomics and Progenesis LC-MS analyses: proteins identified with at least two peptides and showing changes statistically significant (ANOVA; p ≤ 0.05) and above a biologically relevant selected threshold (fold ≥ 2) between treatments are listed. The comparison between Fe-deficient, Mn-deficient and control xylem sap samples using a multivariate statistical data analysis (Principal Component Analysis, PCA) is also included. Data included in this article are discussed in depth in the research article entitled "Effects of Fe and Mn deficiencies on the protein profiles of tomato ( Solanum lycopersicum) xylem sap as revealed by shotgun analyses" [1]. This dataset is made available to support the cited study as well to extend analyses at a later stage.
The role of micronutrients in the response to ambient air pollutants: Potential mechanisms and suggestions for research design.

PubMed

Miller, Colette N; Rayalam, Srujana

2017-01-01

People living in regions of low socioeconomic status are thought to be prone to higher exposures to environmental pollutants, poor nutrition, and numerous preventable diseases and infections. Poverty correlates with pollution and malnutrition; however, limited studies examined their interrelationship. The well-studied, deleterious health effects attributed to environmental pollutants and poor nutrition may act in combination with produce more severe adverse health outcomes than any one factor alone. Deficiencies in specific nutrients render the body more susceptible to injury which may influence the pathways that serve as the mechanistic responses to ambient air pollutants. This review (1) explores specific micronutrients that are of global concern, (2) explains how these nutrients may impact the body's response to ambient air pollution, and (3) provides guidance on designing animal models of nutritional deficiency. It is likely that those individuals who reside in regions of high ambient air pollution are similarly malnourished. Therefore, it is important that research identifies specific nutrients of concern and their impact in identified regions of high ambient air pollution.
Identification, Prevention and Treatment of Iron Deficiency during the First 1000 Days

PubMed Central

Burke, Rachel M.; Leon, Juan S.; Suchdev, Parminder S.

2014-01-01

Iron deficiency is a global problem across the life course, but infants and their mothers are especially vulnerable to both the development and the consequences of iron deficiency. Maternal iron deficiency during pregnancy can predispose offspring to the development of iron deficiency during infancy, with potentially lifelong sequelae. This review explores iron status throughout these “first 1000 days” from pregnancy through two years of age, covering the role of iron and the epidemiology of iron deficiency, as well as its consequences, identification, interventions and remaining research gaps. PMID:25310252
Predictors of vitamin D deficiency in inflammatory bowel disease and health: A Mississippi perspective

PubMed Central

Pallav, Kumar; Riche, Daniel; May, Warren L; Sanchez, Patrick; Gupta, Nitin K

2017-01-01

AIM To identify the predictors of vitamin D deficiency in patients with and without inflammatory bowel disease (IBD). METHODS Patients with ulcerative colitis (UC) or Crohn’s disease (CD) related diagnostic codes who received medical care at University of Mississippi Medical Center between July 2012 and 2015 were identified. After thorough chart review, we identified patients with biopsy proven IBD who had also been tested for serum 25-hydroxyvitamin D [25(OH)D] concentration. We compared these patients to a previously studied cohort of healthy controls who also had vitamin D concentration checked. Logistic regression analysis was performed to determine the association between vitamin d deficiency and UC, CD, race, age, gender and body mass index (BMI). RESULTS We identified 237 patients with confirmed IBD. Of these, only 211 had a serum 25(OH)D concentrations available in the medical record. The group of healthy controls consisted of 98 individuals with available serum 25(OH)D concentration. 43% of IBD patients were African American (AA). Patients with CD were more likely to have vitamin D concentration checked. Bivariate analysis showed that AA (51% vs 21%, P = 0.00001), subjects with BMI >30 kg/m2 (39% vs 23% P = 0.01) and CD (40% vs 26%, P = 0.04) were more likely to be vitamin D deficient than vitamin D sufficient. Those with Age > 65 were more likely to be vitamin D sufficient (46% vs 15%, P = 0.04). Multiple regression showed that only BMI > 30 kg/m2 and AA race are associated with vitamin D deficiency. CONCLUSION BMI > 30 kg/m2 and AA race are predictive of vitamin D deficiency. Gender, age and diagnosis of IBD are not predictive of vitamin D deficiency. PMID:28216970
Predictors of vitamin D deficiency in inflammatory bowel disease and health: A Mississippi perspective.

PubMed

Pallav, Kumar; Riche, Daniel; May, Warren L; Sanchez, Patrick; Gupta, Nitin K

2017-01-28

To identify the predictors of vitamin D deficiency in patients with and without inflammatory bowel disease (IBD). Patients with ulcerative colitis (UC) or Crohn's disease (CD) related diagnostic codes who received medical care at University of Mississippi Medical Center between July 2012 and 2015 were identified. After thorough chart review, we identified patients with biopsy proven IBD who had also been tested for serum 25-hydroxyvitamin D [25(OH)D] concentration. We compared these patients to a previously studied cohort of healthy controls who also had vitamin D concentration checked. Logistic regression analysis was performed to determine the association between vitamin d deficiency and UC, CD, race, age, gender and body mass index (BMI). We identified 237 patients with confirmed IBD. Of these, only 211 had a serum 25(OH)D concentrations available in the medical record. The group of healthy controls consisted of 98 individuals with available serum 25(OH)D concentration. 43% of IBD patients were African American (AA). Patients with CD were more likely to have vitamin D concentration checked. Bivariate analysis showed that AA (51% vs 21%, P = 0.00001), subjects with BMI >30 kg/m 2 (39% vs 23% P = 0.01) and CD (40% vs 26%, P = 0.04) were more likely to be vitamin D deficient than vitamin D sufficient. Those with Age > 65 were more likely to be vitamin D sufficient (46% vs 15%, P = 0.04). Multiple regression showed that only BMI > 30 kg/m 2 and AA race are associated with vitamin D deficiency. BMI > 30 kg/m 2 and AA race are predictive of vitamin D deficiency. Gender, age and diagnosis of IBD are not predictive of vitamin D deficiency.
Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts.

PubMed

Buchanan, Daniel D; Clendenning, Mark; Rosty, Christophe; Eriksen, Stine V; Walsh, Michael D; Walters, Rhiannon J; Thibodeau, Stephen N; Stewart, Jenna; Preston, Susan; Win, Aung Ko; Flander, Louisa; Ouakrim, Driss Ait; Macrae, Finlay A; Boussioutas, Alex; Winship, Ingrid M; Giles, Graham G; Hopper, John L; Southey, Melissa C; English, Dallas; Jenkins, Mark A

2017-02-01

Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAF V600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Tumour testing to identify Lynch syndrome in two Australian colorectal cancer cohorts

PubMed Central

Eriksen, Stine V.; Walsh, Michael D.; Walters, Rhiannon J.; Thibodeau, Stephen N.; Stewart, Jenna; Preston, Susan; Win, Aung Ko; Flander, Louisa; Ouakrim, Driss Ait; Macrae, Finlay A.; Boussioutas, Alex; Winship, Ingrid M.; Giles, Graham G.; Hopper, John L.; Southey, Melissa C.

2016-01-01

Background and Aim Tumour testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilising a combination of tumour and germline testing approaches. Methods CRCs from 813 patients diagnosed with CRC <60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry (IHC), microsatellite instability (MSI), BRAFV600E somatic mutation and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and MLPA) was performed on germline DNA of patients with MMR-deficient tumours and a subset of MMR-proficient CRCs. Results Of the 813 ACCFR probands, 90 probands demonstrated tumour MMR-deficiency (11.1%) and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR-deficiency was identified in the tumours of 103 probands (12.5%) and 7 had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 22.3% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimised by IHC screening of CRC diagnosed before 70 years. A significant proportion of MMR-deficient CRCs will have unknown aetiology (Lynch-like) proving problematic for clinical management. PMID:27273229
Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity.

PubMed

Rochford, Rosemary; Ohrt, Colin; Baresel, Paul C; Campo, Brice; Sampath, Aruna; Magill, Alan J; Tekwani, Babu L; Walker, Larry A

2013-10-22

Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.
Academic Deficiency: Student Experiences of Institutional Labeling

ERIC Educational Resources Information Center

Barouch-Gilbert, Abraham

2015-01-01

Limited existing research examines how undergraduate students in the United States experience the process of being identified as deficient due to their academic performance. The purpose of this phenomenological study was to explore the lived experiences of college students on academic probation who were labeled academically deficient. Students…
Protein profile of Beta vulgaris leaf apoplastic fluid and changes induced by Fe deficiency and Fe resupply

PubMed Central

Ceballos-Laita, Laura; Gutierrez-Carbonell, Elain; Lattanzio, Giuseppe; Vázquez, Saul; Contreras-Moreira, Bruno; Abadía, Anunciación; Abadía, Javier; López-Millán, Ana-Flor

2015-01-01

The fluid collected by direct leaf centrifugation has been used to study the proteome of the sugar beet apoplastic fluid as well as the changes induced by Fe deficiency and Fe resupply to Fe-deficient plants in the protein profile. Plants were grown in Fe-sufficient and Fe-deficient conditions, and Fe resupply was carried out with 45 μM Fe(III)-EDTA for 24 h. Protein extracts of leaf apoplastic fluid were analyzed by two-dimensional isoelectric focusing-SDS-PAGE electrophoresis. Gel image analysis revealed 203 consistent spots, and proteins in 81% of them (164) were identified by nLC-MS/MS using a custom made reference repository of beet protein sequences. When redundant UniProt entries were deleted, a non-redundant leaf apoplastic proteome consisting of 109 proteins was obtained. TargetP and SecretomeP algorithms predicted that 63% of them were secretory proteins. Functional classification of the non-redundant proteins indicated that stress and defense, protein metabolism, cell wall and C metabolism accounted for approximately 75% of the identified proteome. The effects of Fe-deficiency on the leaf apoplast proteome were limited, with only five spots (2.5%) changing in relative abundance, thus suggesting that protein homeostasis in the leaf apoplast fluid is well-maintained upon Fe shortage. The identification of three chitinase isoforms among proteins increasing in relative abundance with Fe-deficiency suggests that one of the few effects of Fe deficiency in the leaf apoplast proteome includes cell wall modifications. Iron resupply to Fe deficient plants changed the relative abundance of 16 spots when compared to either Fe-sufficient or Fe-deficient samples. Proteins identified in these spots can be broadly classified as those responding to Fe-resupply, which included defense and cell wall related proteins, and non-responsive, which are mainly protein metabolism related proteins and whose changes in relative abundance followed the same trend as with Fe-deficiency. PMID:25852707
Assessing urban potential flooding risk and identifying effective risk-reduction measures.

PubMed

Cherqui, Frédéric; Belmeziti, Ali; Granger, Damien; Sourdril, Antoine; Le Gauffre, Pascal

2015-05-01

Flood protection is one of the traditional functions of any drainage system, and it remains a major issue in many cities because of economic and health impact. Heavy rain flooding has been well studied and existing simulation software can be used to predict and improve level of protection. However, simulating minor flooding remains highly complex, due to the numerous possible causes related to operational deficiencies or negligent behaviour. According to the literature, causes of blockages vary widely from one case to another: it is impossible to provide utility managers with effective recommendations on how to improve the level of protection. It is therefore vital to analyse each context in order to define an appropriate strategy. Here we propose a method to represent and assess the flooding risk, using GIS and data gathered during operation and maintenance. Our method also identifies potential management responses. The approach proposed aims to provide decision makers with clear and comprehensible information. Our method has been successfully applied to the Urban Community of Bordeaux (France) on 4895 interventions related to flooding recorded during the 2009-2011 period. Results have shown the relative importance of different issues, such as human behaviour (grease, etc.) or operational deficiencies (roots, etc.), and lead to identify corrective and proactive. This study also confirms that blockages are not always directly due to the network itself and its deterioration. Many causes depend on environmental and operating conditions on the network and often require collaboration between municipal departments in charge of roads, green spaces, etc. Copyright © 2015 Elsevier B.V. All rights reserved.
Glucose-6-phosphate dehydrogenase deficiency in Tunisia: molecular data and phenotype-genotype association.

PubMed

Laouini, N; Bibi, A; Ammar, H; Kazdaghli, K; Ouali, F; Othmani, R; Amdouni, S; Haloui, S; Sahli, C A; Jouini, L; Hadj Fredj, S; Siala, H; Ben Romdhane, N; Toumi, N E; Fattoum, S; Messsaoud, T

2013-02-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect. In this study, we aimed to perform a molecular investigation of G6PD deficiency in Tunisia and to associate clinical manifestations and the degree of deficiency with the genotype. A total of 161 Tunisian subjects of both sexes were screened by spectrophotometric assay for enzyme activity. Out of these, 54 unrelated subjects were selected for screening of the most frequent mutations in Tunisia by PCR/RFLP, followed by size-based separation of double-stranded fragments under non-denaturing conditions on a denaturing high performance liquid chromatography system. Of the 56 altered chromosomes examined, 75 % had the GdA(-) mutation, 14.28 % showed the GdB(-) mutation and no mutations were identified in 10.72 % of cases. Hemizygous males with GdA(-) mutation were mostly of class III, while those with GdB(-) mutation were mainly of class II. The principal clinical manifestation encountered was favism. Acute hemolytic crises induced by drugs or infections and neonatal jaundice were also noted. Less severe clinical features such as low back pain were present in heterozygous females and in one homozygous female. Asymptomatic individuals were in majority heterozygote females and strangely one hemizygous male. The spectrum of mutations seems to be homogeneous and similar to that of Mediterranean countries; nevertheless 10.72 % of cases remain with undetermined mutation thus suggesting a potential heterogeneity of the deficiency at the molecular level. On the other hand, we note a better association of the molecular defects with the severity of the deficiency than with clinical manifestations.
Liver failure with coagulopathy, hyperammonemia and cyclic vomiting in a toddler revealed to have combined heterozygosity for genes involved with ornithine transcarbamylase deficiency and Wilson disease.

PubMed

Mira, Valerie; Boles, Richard G

2012-01-01

A girl with a 2 month history of cyclic episodes of vomiting, diarrhea, and lethargy lasting 2-3 days each presented with acute hepatopathy (ALT 3,500 IU/L) with coagulopathy (PT 55 s) and hyperammonemia (207 μmol/L) at age 1½ years. Biochemical and molecular analyzes revealed ornithine transcarbamylase (OTC) deficiency. While laboratory signs of mild hepatocellular dysfunction are common in OTC deficiency, substantial liver failure with coagulopathy is generally not seen, although four others cases have been reported, three of which presented with cyclic vomiting. Further evaluation in our case revealed elevated urine (198.8 μg/g creatinine) and liver (103 μg/g dry weight) copper content, and a heterozygous mutation in the Wilson disease gene, ATP7B. Our patient, now aged 5 years, has remained in excellent health with normal growth and development on fasting avoidance, a modified vegan diet, and sodium phenylbutyrate.These five cases demonstrate that generalized liver dysfunction/failure is a potential serious complication of OTC deficiency, although not a common one, and suggests that an ALT and PT should be obtained in OTC patients during episodes of hyperammonemia. Cyclic vomiting is a known presentation of OTC deficiency; it is not known if comorbid liver failure predisposes toward this phenotype. We propose that the heterozygote state in ATP7B increases the liver copper content, thus predisposing our patient with OTC deficiency to develop liver failure during a hyperammonemic episode. Our present case is an example of the opportunity of molecular diagnostics to identify putative modifier genes in patients with atypical presentations of genetic disorders.
Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children

PubMed Central

Gozes, I; Van Dijck, A; Hacohen-Kleiman, G; Grigg, I; Karmon, G; Giladi, E; Eger, M; Gabet, Y; Pasmanik-Chor, M; Cappuyns, E; Elpeleg, O; Kooy, R F; Bedrosian-Sermone, S

2017-01-01

A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex- and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan. PMID:28221363
Zn uptake, translocation and grain Zn loading in rice (Oryza sativa L.) genotypes selected for Zn deficiency tolerance and high grain Zn

PubMed Central

Impa, Somayanda M.; Morete, Mark J.; Ismail, Abdelbagi M.; Schulin, Rainer; Johnson-Beebout, Sarah E.

2013-01-01

Zn deficiency is a widespread problem in rice (Oryza sativa L.) grown under flooded conditions, limiting growth and grain Zn accumulation. Genotypes with Zn deficiency tolerance or high grain Zn have been identified in breeding programmes, but little is known about the physiological mechanisms conferring these traits. A protocol was developed for growing rice to maturity in agar nutrient solution (ANS), with optimum Zn-sufficient growth achieved at 1.5 μM ZnSO4.7H2O. The redox potential in ANS showed a decrease from +350 mV to −200 mV, mimicking the reduced conditions of flooded paddy soils. In subsequent experiments, rice genotypes contrasting for Zn deficiency tolerance and grain Zn were grown in ANS with sufficient and deficient Zn to assess differences in root uptake of Zn, root-to-shoot Zn translocation, and in the predominant sources of Zn accumulation in the grain. Zn efficiency of a genotype was highly influenced by root-to-shoot translocation of Zn and total Zn uptake. Translocation of Zn from root to shoot was more limiting at later growth stages than at the vegetative stage. Under Zn-sufficient conditions, continued root uptake during the grain-filling stage was the predominant source of grain Zn loading in rice, whereas, under Zn-deficient conditions, some genotypes demonstrated remobilization of Zn from shoot and root to grain in addition to root uptake. Understanding the mechanisms of grain Zn loading in rice is crucial in selecting high grain Zn donors for target-specific breeding and also to establish fertilizer and water management strategies for achieving high grain Zn. PMID:23698631

Prevalence and molecular basis of glucose-6-phosphate dehydrogenase deficiency in Afghan populations: implications for treatment policy in the region

PubMed Central

2013-01-01

Background Glucose-6-phosphate dehydrogenase deficiency (G6PD), an x-linked inherited enzymopathy, is a barrier to malaria control because primaquine cannot be readily applied for radical cure in individuals with the condition. In endemic areas, including in Afghanistan, the G6PD status of vivax patients is not routinely determined so the drug is rarely, if ever, prescribed even though it is included as a recommended treatment in local, regional and global guidelines. This study assessed the prevalence and genotype of G6PD deficiency in Afghan populations and examined the need for routine G6PD testing as a malaria treatment and control tool. Methods A cross-sectional household survey was conducted using random sampling in five Afghan cities to determine the prevalence of G6PD deficiency in Afghan ethnic groups. Filter-paper blood spots were analysed for phenotypic G6PD deficiency using a fluorescent spot test. Molecular analysis was conducted to identify the genetic basis of the disorder. Results Overall, 45/1,436 (3.1%) people were G6PD deficient, 36/728 (5.0%) amongst males and 9/708 (1.3%) amongst females. Amongst males the prevalence was highest in the Pashtun ethnic group (10%, 26/260) while in Tajik males it was 8/250 (3.2%); in Hazara males it was 1/77 (1.3%) and in Uzbek males is was 0/125. Genetic testing in those with deficiency showed that all were of the Mediterranean type (Med-) characterized by a C-T change at codon 563 of the G6PD gene. Conclusion Prevalence of G6PD deficiency in Afghanistan varies considerably by ethnic group and is predominantly of the Mediterranean type. G6PD deficient individuals are susceptible to potentially severe and life-threatening haemolysis after standard primaquine treatment. If the aim of increasing access to radical treatment of vivax is to be successful reliable G6PD testing needs to be made routinely available within the health system. PMID:23834949
Prevalence and molecular basis of glucose-6-phosphate dehydrogenase deficiency in Afghan populations: implications for treatment policy in the region.

PubMed

Leslie, Toby; Moiz, Bushra; Mohammad, Nader; Amanzai, Omar; Ur Rasheed, Haroon; Jan, Sakhi; Siddiqi, Abdul M; Nasir, Amna; Beg, Mohammad A; Vink, Martijn

2013-07-08

Glucose-6-phosphate dehydrogenase deficiency (G6PD), an x-linked inherited enzymopathy, is a barrier to malaria control because primaquine cannot be readily applied for radical cure in individuals with the condition. In endemic areas, including in Afghanistan, the G6PD status of vivax patients is not routinely determined so the drug is rarely, if ever, prescribed even though it is included as a recommended treatment in local, regional and global guidelines. This study assessed the prevalence and genotype of G6PD deficiency in Afghan populations and examined the need for routine G6PD testing as a malaria treatment and control tool. A cross-sectional household survey was conducted using random sampling in five Afghan cities to determine the prevalence of G6PD deficiency in Afghan ethnic groups. Filter-paper blood spots were analysed for phenotypic G6PD deficiency using a fluorescent spot test. Molecular analysis was conducted to identify the genetic basis of the disorder. Overall, 45/1,436 (3.1%) people were G6PD deficient, 36/728 (5.0%) amongst males and 9/708 (1.3%) amongst females. Amongst males the prevalence was highest in the Pashtun ethnic group (10%, 26/260) while in Tajik males it was 8/250 (3.2%); in Hazara males it was 1/77 (1.3%) and in Uzbek males is was 0/125. Genetic testing in those with deficiency showed that all were of the Mediterranean type (Med-) characterized by a C-T change at codon 563 of the G6PD gene. Prevalence of G6PD deficiency in Afghanistan varies considerably by ethnic group and is predominantly of the Mediterranean type. G6PD deficient individuals are susceptible to potentially severe and life-threatening haemolysis after standard primaquine treatment. If the aim of increasing access to radical treatment of vivax is to be successful reliable G6PD testing needs to be made routinely available within the health system.
Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency–Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus123

PubMed Central

Tran, Phu V; Kennedy, Bruce C; Pisansky, Marc T; Won, Kyoung-Jae; Gewirtz, Jonathan C; Simmons, Rebecca A; Georgieff, Michael K

2016-01-01

Background: Early-life iron deficiency is a common nutrient deficiency worldwide. Maternal iron deficiency increases the risk of schizophrenia and autism in the offspring. Postnatal iron deficiency in young children results in cognitive and socioemotional abnormalities in adulthood despite iron treatment. The rat model of diet-induced fetal-neonatal iron deficiency recapitulates the observed neurobehavioral deficits. Objectives: We sought to establish molecular underpinnings for the persistent psychopathologic effects of early-life iron deficiency by determining whether it permanently reprograms the hippocampal transcriptome. We also assessed the effects of maternal dietary choline supplementation on the offspring’s hippocampal transcriptome to identify pathways through which choline mitigates the emergence of long-term cognitive deficits. Methods: Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (4 g Fe/kg) from gestational day (G) 2 through postnatal day (PND) 7 and an iron-sufficient (IS) diet (200 g Fe/kg) thereafter. Control pups were provided IS diet throughout. Choline (5 g/kg) was given to half the pregnant dams in each group from G11 to G18. PND65 hippocampal transcriptomes were assayed by next generation sequencing (NGS) and analyzed with the use of knowledge-based Ingenuity Pathway Analysis. Real-time polymerase chain reaction was performed to validate a subset of altered genes. Results: Formerly ID rats had altered hippocampal expression of 619 from >10,000 gene loci sequenced by NGS, many of which map onto molecular networks implicated in psychological disorders, including anxiety, autism, and schizophrenia. There were significant interactions between iron status and prenatal choline treatment in influencing gene expression. Choline supplementation reduced the effects of iron deficiency, including those on gene networks associated with autism and schizophrenia. Conclusions: Fetal-neonatal iron deficiency reprograms molecular networks associated with the pathogenesis of neurologic and psychological disorders in adult rats. The positive response to prenatal choline represents a potential adjunctive therapeutic supplement to the high-risk group. PMID:26865644
[Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

PubMed

Woehrle, D; Martinez, M; Bolliger, D

2016-10-01

A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.
Newborn screening of glucose-6-phosphate dehydrogenase deficiency in Guangxi, China: determination of optimal cutoff value to identify heterozygous female neonates.

PubMed

Fu, Chunyun; Luo, Shiyu; Li, Qifei; Xie, Bobo; Yang, Qi; Geng, Guoxing; Lin, Caijuan; Su, Jiasun; Zhang, Yue; Wang, Jin; Qin, Zailong; Luo, Jingsi; Chen, Shaoke; Fan, Xin

2018-01-16

The aim of this study is to assess the disease incidence and mutation spectrum of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Guangxi, China, and to determine an optimal cutoff value to identify heterozygous female neonates. A total of 130, 635 neonates were screened from the year of 2013 to 2017. Neonates suspected for G6PD deficiency were further analyzed by quantitatively enzymatic assay and G6PD mutation analysis. The overall incidence of G6PD deficiency was 7.28%. A total of 14 G6PD mutations were identified, and different mutations lead to varying levels of G6PD enzymatic activities. The best cut-off value of G6PD activity in male subjects is 2.2 U/g Hb, same as conventional setting. In female population, however, the cut-off value is found to be 2.8 U/g Hb (sensitivity: 97.5%, specificity: 87.7%, AUC: 0.964) to best discriminate between normal and heterozygotes, and 1.6 U/g Hb (sensitivity: 82.2%, specificity: 85.9%, AUC: 0.871) between heterozygotes and deficient subjects. In conclusion, we have conducted a comprehensive newborn screening of G6PD deficiency in a large cohort of population from Guangxi, China, and first established a reliable cut-off value of G6PD activity to distinguish heterozygous females from either normal or deficient subjects.
Iodine Deficiency in Australia: Be Alarmed. Opinions & Perspectives

ERIC Educational Resources Information Center

McElduff, Aidan; Beange, Helen

2004-01-01

Iodine deficiency, the leading preventable cause of intellectual impairment in the world (World Health Organization, 1999), has reappeared in Australia. Recently, we identified the re-emergence of iodine deficiency in Sydney (Gunton, Hams, Fiegert & McElduff, 1999). This has been confirmed locally (Li, Ma, Boyages & Eastman, 2001) and…
The Relationship of Health and Nutrition to the Learning Process.

ERIC Educational Resources Information Center

Norwood, Glenda R.

In addition to identifying the causes and physical effects of various nutritional deficiencies, this discussion describes the effects of each deficiency on the learning process. The recommended daily food intake for children and teenagers is also noted. Eight types of nutritional deficiency are discussed in detail: (1) malnutrition (both…
Heterogeneity of G6PD deficiency prevalence in Mozambique: a school-based cross-sectional survey in three different regions.

PubMed

Galatas, Beatriz; Mabote, Lurdes; Simone, Wilson; Matambisso, Gloria; Nhamussua, Lidia; Mañú-Pereira, María Del Mar; Menéndez, Clara; Saute, Francisco; Macete, Eusebio; Bassat, Quique; Alonso, Pedro; Aide, Pedro

2017-01-19

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked hereditary enzymatic abnormality that affects more than 400 million people worldwide. Most deficient individuals do not manifest any symptoms; however, several precipitant agents-such as fava intake, infections, or several drugs-may trigger acute haemolytic anaemia. Countries should be informed of the prevalence of this enzymatic anomaly within their borders, in order to make safe and appropriate national decisions regarding the use of potentially unsafe drugs for G6PD deficient individuals. A school-based cross-sectional survey was conducted in three districts in Mozambique, namely Manhiça, located in the south; Mocuba in the centre; and Pemba in the northern tip of the country. G6PD deficiency was evaluated using the CareStart™ diagnostic test, and enzyme activity levels were measured through fluorescence spectrophotometry in deficient individuals. Chi squared and ANOVA tests were used to assess prevalence and mean enzyme activity differences, and logistic regression was used to identify risk factors associated to the deficiency. G6PD deficiency prevalence estimates were lowest in the northern city of Pemba (8.3%) and among Emakhuwas and Shimakondes, and higher in the centre and southern regions of the country (16.8 and 14.6%, respectively), particularly among Elomwes and Xichanganas. G6PD deficiency was significantly more prevalent among male students than females (OR = 1.4, 95% CI 1.0-1.8, p = 0.02), although enzyme activity levels were not different among deficient individuals from either gender group. Finally, median deficiency levels were found to be more severe among the deficient students from the north (0.7 U/gHg [0.2-0.7] p < 0.001) and south (0.7 U/gHg [0.5-2.5]), compared to those from the centre (1.4 U/gHg [0.6-2.1]). These findings suggest that Mozambique, as a historically high malaria-endemic country has considerable levels of G6PD deficiency, that vary significantly across the country. This should be considered when planning national strategies for the use of licensed drugs that may be associated to haemolysis among G6PD individuals, or prior to the performance of future trials using primaquine and other 8-aminoquinolines derivatives. Registration Number CISM local ethics committee (CIBS-25/013, 4th of December 2013), and the National Ethics Committee of Mozambique (IRB00002657, 28th of February 2014).
Defense Logistics Agency Can Improve Its Product Quality Deficiency Report Processing

DTIC Science & Technology

2015-07-01

Contracts for M2 Machine Gun Spare Parts in Support of Operations in Southwest Asia,” January 11, 2010 Appendixes DODIG-2015-140 │ 29 Appendix B...personnel are adequately processing product quality deficiency reports and identifying the root cause for defective spare parts . This is the first...quality deficiency report program and prevents meaningful analysis of the primary causes of spare- part quality deficiencies. In addition, the
Preoperative vitamin D level as predictor of post-thyroidectomy hypocalcemia in patients sustaining transient parathyroid injury.

PubMed

Danan, Deepa; Shonka, David C

2017-07-01

Several studies have sought to identify predictors of postoperative hypocalcemia after total thyroidectomy; however, there have been conflicting results regarding the impact of preoperative vitamin D deficiency. The medical records of patients undergoing total thyroidectomy were retrospectively reviewed. The number of parathyroid glands identified or reimplanted at the time of surgery was used as a marker of transient parathyroid gland damage. Sixty-seven patients were included in the study. Vitamin D deficiency was a significant predictor of hypocalcemia in patients in whom ≥3 parathyroid glands were identified, but not in patients in whom 0-2 parathyroid glands were identified intraoperatively (odds ratio [OR] 5.8; P = .036). Vitamin D deficiency is a significant predictor of postoperative hypocalcemia in patients in whom ≥3 parathyroid glands are identified intraoperatively, but not in patients who sustain minimal transient damage to the parathyroid glands. © 2017 Wiley Periodicals, Inc.
Long-Lasting Neural and Behavioral Effects of Iron Deficiency in Infancy

PubMed Central

Lozoff, Betsy; Beard, John; Connor, James; Felt, Barbara; Georgieff, Michael; Schallert, Timothy

2006-01-01

Infants are at high risk for iron deficiency and iron-deficiency anemia. This review summarizes evidence of long-term effects of iron deficiency in infancy. Follow-up studies from preschool age to adolescence report poorer cognitive, motor, and social-emotional function, as well as persisting neurophysiologic differences. Research in animal models points to mechanisms for such long-lasting effects. Potential mechanisms relate to effects of iron deficiency during brain development on neurometabolism, myelination, and neurotransmitter function. PMID:16770951
A strategic approach to the unfinished fortification agenda: feasibility, costs, and cost-effectiveness analysis of fortification programs in 48 countries.

PubMed

Fiedler, John L; Macdonald, Barbara

2009-12-01

Food fortification is a promising strategy for combating micronutrient deficiencies, which plague one-third of the world's population. Which foods to fortify, with which micronutrients, and in which countries remain essential questions that to date have not been addressed at the global level. To provide a tool for international agencies to identify and organize the next phase of the unfinished global fortification agenda by prioritizing roughly 250 potential interventions in 48 priority countries. By explicitly defining the structure and operations of the fortification interventions in a detailed and transparent manner, and incorporating a substantial amount of country-specific data, the study also provides a potentially useful starting point for policy discussions in each of the 48 countries, which--it is hoped--will help to catalyze the development of public-private partnerships and accelerate the introduction of fortification and reduction of micronutrient deficiencies. Forty-eight high-priority countries were identified, and the feasibility of fortifying vegetable oil and sugar with vitamin A and fortifying wheat flour and maize flour with two alternative multiple micronutrient formulations was assessed. One hundred twenty-two country-, food-, and fortification formulation-specific interventions were assessed to be feasible, and the costs of each intervention were estimated. Assuming a 30% reduction in the micronutrient deficiencies of the persons consuming the food, the number of disability-adjusted life years (DALYs) saved by each of the programs was estimated. The cost per DALY saved was calculated for each of the 122 interventions, and the interventions were rank-ordered by cost-effectiveness. It is estimated that the 60 most cost-effective interventions would carry a 10-year price tag of US$1 billion and have costs per DALY saved ranging from US$1 to US$134. The single "best bet" intervention--i.e., the most cost-effective intervention--in each of the 48 countries was identified. This study provides a detailed, transparent, evidence-based approach to defining and estimating the costs and cost-effectiveness of the unfinished global fortification agenda in the 48 priority countries. Other considerations in designing a strategic approach to the unfinished global fortification agenda are also discussed.
Frequent life-threatening laryngeal attacks in two Croatian families with hereditary angioedema due to C1 inhibitor deficiency harbouring a novel frameshift mutation in SERPING1.

PubMed

Karadža-Lapić, Ljerka; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Cikojević, Draško; Lozić, Bernarda; Rijavec, Matija

2016-11-01

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease caused by mutations in the SERPING1 gene. It can affect many regions in the body, but potentially life-threatening laryngeal oedemas are of concern. Twenty-three subjects from two families were recruited for clinical data evaluation and molecular analysis at General Hospital Šibenik, Croatia. Decreased levels of C1 inhibitor were detected in 12 adult patients and three young asymptomatic persons. The same novel deletion of two nucleotides on exon 3 (c.74_75delAT) was identified in all of them. A history of laryngeal oedema was present in 10 patients (83%), and all patients reported laryngeal attacks at least once a year. The delay in diagnosis decreased noticeably from the first to the last generation. We identified a novel causative mutation in SERPING1 in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship. Key messages Hereditary angioedema due to C1 inhibitor deficiency is a rare autosomal dominant disease caused by mutations in the SERPING1 gene, and laryngeal oedema is of concern because it can cause death by asphyxiation. A novel causative mutation in SERPING1, a deletion of two nucleotides on exon 3 (c.74_75delAT), was identified in several affected members of two apparently unrelated families with a high frequency of laryngeal oedema. Molecular analysis of large C1-INH-HAE families will provide new insights on the genotype-phenotype relationship because it appears that the mutation type may affect disease severity.
Spectrum of primary immunodeficiency disorders in Sri Lanka

PubMed Central

2013-01-01

Background While primary immunodeficiencies (PID has been recognized in the west for decades, recognition has been delayed in the third world. This study attempts to detail the spectrum of PID, the therapy provided, and constraints in the diagnosis and treatment in a middle income country such as Sri Lanka. Methods Nine hundred and forty two patients with recurrent infections and features suggestive of immune deficiency, referred from the entire country in a 4 year period, to the sole immunology unit in Sri Lanka were included. The following tests were performed. Full blood counts, serum Immunoglobulin and complement C3 and C4 levels, functional antibody levels, enumeration of lymphocyte subsets, in vitro and in vivo T cell functional assays,, nitroblue tetrazolium assay to diagnose chronic granulomatous disease, hair shaft assay to diagnose Griscelli syndrome. Sequencing of the common gamma chain to identify x linked severe combined immune deficiency, and X linked agammaglobulinemia was confirmed by assaying for Btk mutations by single sequence conformation polymorphism. HIV/AIDS was excluded in all patients. Results Seventy three patients were diagnosed with a primary immune deficiency. The majority (60.27%) had antibody deficiency. Common variable immune deficiency was the commonest (28.76%), followed by X linked agammaglobulinemia (XLA) (20.54%). Five patients had possible hyper IgM syndrome. Ten patients had severe combined immune deficiency (SCID), including 2 with x linked SCID, in addition to DiGeorge syndrome (2), ataxia telangiectasia (6), autosomal dominant hyper IgE syndrome (2), chronic granulomatous disease (4), leucocyte adhesion deficiency type 1 (2) and Griscelli syndrome (3). Patients with autoinflammatory, innate immune and complement defects could not be identified due to lack of facilities. Conclusions Antibody deficiency is the commonest PID, as in the west.IgA deficiency is rare. Autoinflammatory diseases, innate immune and complement deficiencies could not be identified due to lack of diagnostic facilities. Lack of awareness of PID among adult physicians result in delay in treatment of adult patients. While treatment of antibody deficiencies provided in state hospitals has extended life expectancy, there is no treatment available for severe T cell defects. PMID:24373416
Pharmaceutical issues during the review of European Marketing Authorisation Applications in Malta.

PubMed

Chetcuti, Michael; Serracino-Inglott, Anthony; Flores, Gavril; Borg, John J

2018-07-01

The aim of this study was to identify pharmaceutical issues encountered during regulatory review in European Procedures. A database of issues from Day 70 assessment reports of 150 EU procedures was compiled; most procedures were for generics (108). Frequencies of common deficiencies have been calculated and summarised for use of all stakeholders. Out of the 150 procedures reviewed, covering 309 products, a total of 4796 concerns were identified. Of these concerns, 167 were Potential Serious Risks to Public Health, 67 were raised on drug substance and 100 on the drug product. The distribution of total concerns was as follows: 2168 concerns on drug substance and 2584 on drug product. Most concerns raised were on control of drug substance and drug product (834 & 626 for 3.2.S.4 and 3.2.P.5, respectively), followed by concerns on the manufacturing (482 & 564 for 3.2.S.2 and 3.2.P.3, respectively) and stability 147 & 398 for 3.2.S.7 and 3.2.P.8, respectively). In conclusion, the frequencies and trends of identified deficiencies together with their impact were discussed from a regulatory point of view. The main findings indicate that applicants would benefit from following published guidelines so that delays in the registration of medicines could be avoided.
A Synthetic Interaction Screen Identifies Factors Selectively Required for Proliferation and TERT Transcription in p53-Deficient Human Cancer Cells

PubMed Central

Park, Sung Mi; Zhu, Lihua J.; Debily, Marie-anne; Kittler, Ellen L. W.; Zapp, Maria L.; Lapointe, David; Gobeil, Stephane; Virbasius, Ching-Man; Green, Michael R.

2012-01-01

Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)–based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53−) human cancer cells. We find that compared to p53-competent (p53+) human cancer cell lines, diverse p53− human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53− cells, RNAi–mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit TERT leading to growth arrest, which can be reversed by ectopic TERT expression. Chromatin immunoprecipitation analysis reveals that ETV1 binds to a region downstream of the TERT transcriptional start-site in p53− but not p53+ cells. We find that the role of ATR is to phosphorylate and thereby stabilize ETV1. Our collective results identify a regulatory pathway involving ETV1, ATR, and TERT that is preferentially important for proliferation of diverse p53− cancer cells. PMID:23284306
The Evidence-Based Evaluation of Iron Deficiency Anemia.

PubMed

Hempel, Eliana V; Bollard, Edward R

2016-09-01

Anemia is a prevalent disease with multiple possible etiologies and resultant complications. Iron deficiency anemia is a common cause of anemia and is typically due to insufficient intake, poor absorption, or overt or occult blood loss. Distinguishing iron deficiency from other causes of anemia is integral to initiating the appropriate treatment. In addition, identifying the underlying cause of iron deficiency is also necessary to help guide management of these patients. We review the key components to an evidence-based, cost-conscious evaluation of suspected iron deficiency anemia. Copyright © 2016 Elsevier Inc. All rights reserved.
Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update.

PubMed

Mohn, Emily S; Kern, Hua J; Saltzman, Edward; Mitmesser, Susan H; McKay, Diane L

2018-03-20

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug-nutrient interactions is quite limited. A comprehensive, updated review of the potential drug-nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.
Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update

PubMed Central

Mohn, Emily S.; Kern, Hua J.; Saltzman, Edward; Mitmesser, Susan H.; McKay, Diane L.

2018-01-01

The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is quite limited. A comprehensive, updated review of the potential drug–nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care. PMID:29558445
Impact of Fetal-Neonatal Iron Deficiency on Recognition Memory at 2 Months of Age.

PubMed

Geng, Fengji; Mai, Xiaoqin; Zhan, Jianying; Xu, Lin; Zhao, Zhengyan; Georgieff, Michael; Shao, Jie; Lozoff, Betsy

2015-12-01

To assess the effects of fetal-neonatal iron deficiency on recognition memory in early infancy. Perinatal iron deficiency delays or disrupts hippocampal development in animal models and thus may impair related neural functions in human infants, such as recognition memory. Event-related potentials were used in an auditory recognition memory task to compare 2-month-old Chinese infants with iron sufficiency or deficiency at birth. Fetal-neonatal iron deficiency was defined 2 ways: high zinc protoporphyrin/heme ratio (ZPP/H > 118 μmol/mol) or low serum ferritin (<75 μg/L) in cord blood. Late slow wave was used to measure infant recognition of mother's voice. Event related potentials patterns differed significantly for fetal-neonatal iron deficiency as defined by high cord ZPP/H but not low ferritin. Comparing 35 infants with iron deficiency (ZPP/H > 118 μmol/mol) to 92 with lower ZPP/H (iron-sufficient), only infants with iron sufficiency showed larger late slow wave amplitude for stranger's voice than mother's voice in frontal-central and parietal-occipital locations, indicating the recognition of mother's voice. Infants with iron sufficiency showed electrophysiological evidence of recognizing their mother's voice, whereas infants with fetal-neonatal iron deficiency did not. Their poorer auditory recognition memory at 2 months of age is consistent with effects of fetal-neonatal iron deficiency on the developing hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

The Comparative Efficacy of the Masquelet versus Titanium Mesh Cage Reconstruction Techniques for the Treatment of Large Long Bone Deficiencies

DTIC Science & Technology

2016-10-01

include 9 MT, 7 TMCT. Within the last 12-month study period, 8 patients were enrolled, 2 completed the study, 1 was withdrawn, and 11 are actively ...TMCT) are being actively followed, and their study courses are uneventful. There are 3 additional potentially eligible study patients identified...Uneventfully Subjects Actively Participating Subjects Removed from Trial Continuation Masquelet 9 2 6 1 Cage 7 0 5 2 Total: 16
The causes of hypopituitarism in the absence of abnormal pituitary imaging.

PubMed

Wilson, V; Mallipedhi, A; Stephens, J W; Redfern, R M; Price, D E

2014-01-01

Hypopituitarism in the absence of a history of pituitary pathology or abnormal pituitary imaging is rare. To identify the cause of hypopituitarism in individuals in whom pituitary imaging was normal. Retrospective analysis of electronic patient record. A review of the pituitary function in the 506 patients on the Morriston Hospital pituitary database revealed 230 had some degree of hypopituitarism and of these, 21 (9%) had normal pituitary imaging. Of this group, six patients had a past medical history of subarachnoid haemorrhage, head injury or meningitis, and mainly suffered from a deficiency of antidiuretic hormone. One patient had a stroke resulting in multiple anterior hormone deficiencies and six individuals had idiopathic cranial diabetes insipidus (DI). Subsequent investigations of the remaining eight patients with normal pituitary imaging revealed that two had neurosarcoidosis both of whom had panhypopituitarism. Four patients had haemochromatosis which resulted in gonadotropin deficiency in two, DI in one and panhypopituitarism in the other. There were two individuals with confirmed hypopituitarism and multiple hormone deficiencies in which no cause could be identified. These results show that hypopituitarism in the absence of pituitary pathology or an identifiable cause is rare. In patients with multiple anterior pituitary hormone deficiencies haemochromatosis and sarcoidosis should be considered.
Task management skills and their deficiencies during care delivery in simulated medical emergency situation: A classification.

PubMed

Morineau, Thierry; Chapelain, Pascal; Quinio, Philippe

2016-06-01

Our objective was to develop the analysis of task management skills by proposing a framework classifying task management stages and deficiencies. Few studies of non-technical skills have detailed the components of task management skills through behavioural markers, despite their central role in care delivery. A post hoc qualitative behavioural analysis was performed of recordings made of professional training sessions based upon simulated scenarios. Four recorded sessions in a high-fidelity simulation setting were observed and recorded. Two scenarios were used (cardiac arrest and respiratory failure), and there were two training sessions per scenario. Four types of task management deficiencies were identified with regards to task constraints: constraint relaxation, unsatisfied constraints, additional constraints and constraint transgression. Both equipment and space constraints were also identified. The lack of prerequisite actions when preparing the environment, corequisite actions for equipment and protocol monitoring, or postrequisite actions to restore the environment were associated with task management deficiencies. Deficiencies in task management behaviours can be identified in simulated as well as actual medical emergency settings. This framework opens perspectives for both training caregivers and designing ergonomic work situations. Copyright © 2015 Elsevier Ltd. All rights reserved.
Nicorandil, a Nitric Oxide Donor and ATP-Sensitive Potassium Channel Opener, Protects Against Dystrophin-Deficient Cardiomyopathy

PubMed Central

Afzal, Muhammad Z.; Reiter, Melanie; Gastonguay, Courtney; McGivern, Jered V.; Guan, Xuan; Ge, Zhi-Dong; Mack, David L.; Childers, Martin K.; Ebert, Allison D.; Strande, Jennifer L.

2016-01-01

Background Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart. Methods and Results Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide–cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart. Conclusion Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy. PMID:26940570
Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.

PubMed

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E; Seidman, J G; Pu, William T; Wang, Da-Zhi

2015-11-02

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.
Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

PubMed Central

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E.; Seidman, J.G.; Pu, William T.; Wang, Da-Zhi

2015-01-01

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression. PMID:26436652
Oligomerization of Clostridium perfringens Epsilon Toxin Is Dependent upon Caveolins 1 and 2

PubMed Central

Fennessey, Christine M.; Sheng, Jinsong; Rubin, Donald H.; McClain, Mark S.

2012-01-01

Evidence from multiple studies suggests that Clostridium perfringens ε-toxin is a pore-forming toxin, assembling into oligomeric complexes in the plasma membrane of sensitive cells. In a previous study, we used gene-trap mutagenesis to identify mammalian factors contributing to toxin activity, including caveolin-2 (CAV2). In this study, we demonstrate the importance of caveolin-2 and its interaction partner, caveolin-1 (CAV1), in ε-toxin-induced cytotoxicity. Using CAV2-specific shRNA in a toxin-sensitive human kidney cell line, ACHN, we confirmed that cells deficient in CAV2 exhibit increased resistance to ε-toxin. Similarly, using CAV1-specific shRNA, we demonstrate that cells deficient in CAV1 also exhibit increased resistance to the toxin. Immunoprecipitation of CAV1 and CAV2 from ε-toxin-treated ACHN cells demonstrated interaction of both CAV1 and -2 with the toxin. Furthermore, blue-native PAGE indicated that the toxin and caveolins were components of a 670 kDa protein complex. Although ε-toxin binding was only slightly perturbed in caveolin-deficient cells, oligomerization of the toxin was dramatically reduced in both CAV1- and CAV2-deficient cells. These results indicate that CAV1 and -2 potentiate ε-toxin induced cytotoxicity by promoting toxin oligomerization – an event which is requisite for pore formation and, by extension, cell death. PMID:23056496
Oligomerization of Clostridium perfringens epsilon toxin is dependent upon caveolins 1 and 2.

PubMed

Fennessey, Christine M; Sheng, Jinsong; Rubin, Donald H; McClain, Mark S

2012-01-01

Evidence from multiple studies suggests that Clostridium perfringens ε-toxin is a pore-forming toxin, assembling into oligomeric complexes in the plasma membrane of sensitive cells. In a previous study, we used gene-trap mutagenesis to identify mammalian factors contributing to toxin activity, including caveolin-2 (CAV2). In this study, we demonstrate the importance of caveolin-2 and its interaction partner, caveolin-1 (CAV1), in ε-toxin-induced cytotoxicity. Using CAV2-specific shRNA in a toxin-sensitive human kidney cell line, ACHN, we confirmed that cells deficient in CAV2 exhibit increased resistance to ε-toxin. Similarly, using CAV1-specific shRNA, we demonstrate that cells deficient in CAV1 also exhibit increased resistance to the toxin. Immunoprecipitation of CAV1 and CAV2 from ε-toxin-treated ACHN cells demonstrated interaction of both CAV1 and -2 with the toxin. Furthermore, blue-native PAGE indicated that the toxin and caveolins were components of a 670 kDa protein complex. Although ε-toxin binding was only slightly perturbed in caveolin-deficient cells, oligomerization of the toxin was dramatically reduced in both CAV1- and CAV2-deficient cells. These results indicate that CAV1 and -2 potentiate ε-toxin induced cytotoxicity by promoting toxin oligomerization - an event which is requisite for pore formation and, by extension, cell death.
Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice.

PubMed

Gross, Adi; Benninger, Felix; Madar, Ravit; Illouz, Tomer; Griffioen, Kathleen; Steiner, Israel; Offen, Daniel; Okun, Eitan

2017-04-01

Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE). To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)β. Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE. This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.
25 CFR 170.463 - What should the Secretary do if a design deficiency is identified?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false What should the Secretary do if a design deficiency is identified? 170.463 Section 170.463 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Planning, Design, and Construction of Indian Reservation Roads...
Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity

PubMed Central

Rochford, Rosemary; Ohrt, Colin; Baresel, Paul C.; Campo, Brice; Sampath, Aruna; Magill, Alan J.; Tekwani, Babu L.; Walker, Larry A.

2013-01-01

Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations. PMID:24101478
Effect of substrate nature on the electrochemical deposition of calcium-deficient hydroxyapatites

NASA Astrophysics Data System (ADS)

Gualdrón-Reyes, A. F.; Domínguez-Vélez, V.; Morales-Morales, J. A.; Cabanzo, R.; Meléndez, A. M.

2017-01-01

Calcium phosphates were obtained by reducing nitrate ions to produce hydroxide ions on TiO2/stainless steel and TiO2/titanium electrodes. TiO2 coatings on metallic substrates were prepared by sol-gel dip-coating method. The morphology of deposits was observed by FESEM. Chemical nature of calcium phosphate deposits was identified by Raman micro-spectroscopy and FESEM/EDS microanalysis. Electrochemical behavior of nitrate and nitrite reduction on stainless steel and titanium electrodes was studied by linear sweep voltammetry. In addition, voltammetric study of the calcium phosphate electrodeposition on both electrodes was performed. From these measurements was selected the potential to form a calcium phosphate. A catalytic current associated to nitrate reduction reaction was obtained for stainless steel electrode, leading to significant deposition of calcium phosphate. Ca/P ratio for both substrates was less than 1.67. The formation of calcium deficient hydroxyapatite was confirmed by Raman spectroscopy.
Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome

PubMed Central

Dinwiddie, Darrell L.; Smith, Laurie D.; Miller, Neil A.; Atherton, Andrea M.; Farrow, Emily G.; Strenk, Meghan E.; Soden, Sarah E.; Saunders, Carol J.; Kingsmore, Stephen F.

2015-01-01

Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations. PMID:23631824
Impact of the method of G6PD deficiency assessment on genetic association studies of malaria susceptibility.

PubMed

Johnson, Marla K; Clark, Tamara D; Njama-Meya, Denise; Rosenthal, Philip J; Parikh, Sunil

2009-09-30

Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females). This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria.
Combining suppressive subtractive hybridization and cDNA microarrays to identify dietary phosphorus-responsive genes of the rainbow trout (Oncorhynchus mykiss) kidney.

PubMed

Lake, Jennifer; Gravel, Catherine; Koko, Gabriel Koffi D; Robert, Claude; Vandenberg, Grant W

2010-03-01

Phosphorus (P)-responsive genes and how they regulate renal adaptation to phosphorous-deficient diets in animals, including fish, are not well understood. RNA abundance profiling using cDNA microarrays is an efficient approach to study nutrient-gene interactions and identify these dietary P-responsive genes. To test the hypothesis that dietary P-responsive genes are differentially expressed in fish fed varying P levels, rainbow trout were fed a practical high-P diet (R20: 0.96% P) or a low-P diet (R0: 0.38% P) for 7 weeks. The differentially-expressed genes between dietary groups were identified and compared from the kidney by combining suppressive subtractive hybridization (SSH) with cDNA microarray analysis. A number of genes were confirmed by real-time PCR, and correlated with plasma and bone P concentrations. Approximately 54 genes were identified as potential dietary P-responsive after 7 weeks on a diet deficient in P according to cDNA microarray analysis. Of 18 selected genes, 13 genes were confirmed to be P-responsive at 7 weeks by real-time PCR analysis, including: iNOS, cytochrome b, cytochrome c oxidase subunit II , alpha-globin I, beta-globin, ATP synthase, hyperosmotic protein 21, COL1A3, Nkef, NDPK, glucose phosphate isomerase 1, Na+/H+ exchange protein and GDP dissociation inhibitor 2. Many of these dietary P-responsive genes responded in a moderate way (R0/R20 ratio: <2-3 or >0.5) and in a transient manner to dietary P limitation. In summary, renal adaptation to dietary P deficiency in trout involves changes in the expression of several genes, suggesting a profile of metabolic stress, since many of these differentially-expressed candidates are associated with the cellular adaptative responses. Crown Copyright 2009. Published by Elsevier Inc. All rights reserved.
Identification of boron-deficiency-responsive microRNAs in Citrus sinensis roots by Illumina sequencing

PubMed Central

2014-01-01

Background Boron (B)-deficiency is a widespread problem in many crops, including Citrus. MicroRNAs (miRNAs) play important roles in nutrient deficiencies. However, little is known on B-deficiency-responsive miRNAs in plants. In this study, we first identified miRNAs and their expression pattern in B-deficient Citrus sinensis roots by Illumina sequencing in order to identify miRNAs that might be involved in the tolerance of plants to B-deficiency. Results We isolated 52 (40 known and 12 novel) up-regulated and 82 (72 known and 10 novel) down-regulated miRNAs from B-deficient roots, demonstrating remarkable metabolic flexibility of roots, which might contribute to the tolerance of plants to B-deficiency. A model for the possible roles of miRNAs in the tolerance of roots to B-deficiency was proposed. miRNAs might regulate the adaptations of roots to B-deficiency through following several aspects: (a) inactivating reactive oxygen species (ROS) signaling and scavenging through up-regulating miR474 and down-regulating miR782 and miR843; (b) increasing lateral root number by lowering miR5023 expression and maintaining a certain phenotype favorable for B-deficiency-tolerance by increasing miR394 expression; (c) enhancing cell transport by decreasing the transcripts of miR830, miR5266 and miR3465; (d) improving osmoprotection (miR474) and regulating other metabolic reactions (miR5023 and miR821). Other miRNAs such as miR472 and miR2118 in roots increased in response to B-deficiency, thus decreasing the expression of their target genes, which are involved in disease resistance, and hence, the disease resistance of roots. Conclusions Our work demonstrates the possible roles of miRNAs and related mechanisms in the response of plant roots to B-deficiency. PMID:24885979
Histomorphometric and microchemical characterization of maturing dental enamel in rats fed a boron-deficient diet

USDA-ARS?s Scientific Manuscript database

Few reports are available in the literature on enamel formation under nutritional deficiencies. Continuously erupting rodent incisors have considerable potential to serve as a model system for amelogenesis. Thus, we performed a study to determine the effects of boron (B) deficiency on the maturing d...
Coping strategies and nutritional health in rural Niger: recommendations for consumption of wild plant foods in the Sahel.

PubMed

Glew, Robert S; Vanderjagt, Dorothy

2006-01-01

People who live in food and water deficit regions of Sahelien West Africa employ various coping strategies as they attempt to meet their food and water needs. In this paper we discuss various coping strategies employed by rural Nigeriens living in the Tanout and Mirriya administrative regions of central Niger. In rural Niger people often harvest or buy wild plant foods to eat. Laboratory studies of the nutritional content of these plants indicate that there are benefits to eating wild plant foods. In this study we summarize the results of field research conducted during the summer of 2002 on the use of wild plant foods in three regions of rural central Niger. Comparing local use of various wild plant foods with major nutrition-related health problems including protein deficiency, essential fatty acid deficiency, iron deficiency and iron deficiency anemia, calcium deficiency rickets, and zinc deficiency, suggests potential recommendations for consumption of these plants. However, further research on the bioavailability of these nutrients is needed to confirm the potential benefits of these plants.
Neural cell adhesion molecule-deficient beta-cell tumorigenesis results in diminished extracellular matrix molecule expression and tumour cell-matrix adhesion.

PubMed

Håkansson, Joakim; Xian, Xiaojie; He, Liqun; Ståhlberg, Anders; Nelander, Sven; Samuelsson, Tore; Kubista, Mikael; Semb, Henrik

2005-01-01

To understand by which mechanism neural cell adhesion molecule (N-CAM) limits beta tumour cell disaggregation and dissemination, we searched for potential downstream genes of N-CAM during beta tumour cell progression by gene expression profiling. Here, we show that N-CAM-deficient beta-cell tumorigenesis is associated with changes in the expression of genes involved in cell-matrix adhesion and cytoskeletal dynamics, biological processes known to affect the invasive and metastatic behaviour of tumour cells. The extracellular matrix (ECM) molecules emerged as the primary target, i.e. N-CAM deficiency resulted in down-regulated mRNA expression of a broad range of ECM molecules. Consistent with this result, deficient deposition of major ECM stromal components, such as fibronectin, laminin 1 and collagen IV, was observed. Moreover, N-CAM-deficient tumour cells displayed defective matrix adhesion. These results offer a potential mechanism for tumour cell disaggregation during N-CAM-deficient beta tumour cell progression. Prospective consequences of these findings for the role of N-CAM in beta tumour cell dissemination are discussed.
Retinal degeneration in cats fed casein. IV. The early receptor potential.

PubMed

Berson, E L; Watson, G; Grasse, K L; Szamier, R B

1981-08-01

Electroretinographic studies of casein-fed cats with retinal taurine deficiency revealed that the early receptor potential (ERP) was initially normal in amplitude at a time when the a-wave and b-wave of the electroretinogram were substantially reduced or even nondetectable. The preserved ERP's in these taurine-deficient cats could be correlated with the histologic finding that their outer segments were relatively intact over 90% of the retinal area subtended by the test flash. The sequence of electroretinographic changes in these taurine-deficient cats was also consistent with previous biochemical studies on the normal cat retina that have shown a relatively low concentration of taurine at the level of the outer segments and a higher concentration at the level of the inner segments. The responses in early stages from taurine-deficient cats differed from the responses obtained from vitamin A--deficient cats but resembled those from cats that received an intravitreal injection of ouabain. Similarities and a difference between the responses of taurine-deficient cats and those of patients with early retinitis pigmentosa are considered.

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.

PubMed

Devaraju, P; Yu, J; Eddins, D; Mellado-Lagarde, M M; Earls, L R; Westmoreland, J J; Quarato, G; Green, D R; Zakharenko, S S

2017-09-01

Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.
Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

PubMed Central

Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara; Podszywalow-Bartnicka, Paulina; Maifrede, Silvia; Di Marcantonio, Daniela; Bolton-Gillespie, Elisabeth; Cramer-Morales, Kimberly; Lee, Jaewong; Li, Min; Slupianek, Artur; Gritsyuk, Daniel; Cerny-Reiterer, Sabine; Seferynska, Ilona; Bullinger, Lars; Gorbunova, Vera; Piwocka, Katarzyna; Valent, Peter; Civin, Curt I.; Muschen, Markus; Dick, John E.; Wang, Jean C.Y.; Bhatia, Smita; Bhatia, Ravi; Eppert, Kolja; Minden, Mark D.; Sykes, Stephen M.

2017-01-01

Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase–mediated (DNA-PK–mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK–deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK–deficient quiescent leukemia cells and BRCA/DNA-PK–deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients. PMID:28481221
Development of type 2 diabetes caused by a deficiency of a tRNA(lys) modification.

PubMed

Wei, Fan-Yan; Tomizawa, Kazuhito

2012-01-01

Genetic variations in the cdk5 regulator associated protein 1-like 1 (cdkal1) gene have been identified in whole genome association studies as a risk factor for the development of type 2 diabetes (T2D). A recent study showed that Cdkal1 was a mammalian methythiotransferase, which specifically synthesizes 2-methylthio-N (6)-threonylcarbamoyladenosine (ms (2)t (6)A) at position 37 of tRNA(lys)(UUU). The ms (2)t (6)A modification in tRNA(lys)(UUU) was important for the accurate decoding of its cognate codon. In pancreatic β-cell-specific Cdkal1 knockout (Cdkal1 KO) mice, a deficiency of ms (2)t (6)A caused the mistranslation of a Lys codon in proinsulin, resulting in improper processing. The mice showed a decrease in insulin secretion and glucose intolerance. In addition, the mistranslation contributed to the expression of the endoplasmic reticulum (ER) stress response in Cdkal1-deficient β-cells. Furthermore, Cdkal1 KO mice were hypersensitive to high-fat diet-induced glucose intolerance, as well as the ER stress response. These findings might potentially explain the molecular pathogenesis of T2D in patients carrying Cdkal1 variations.
A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsigos, C.; Arai, K.; Latronico, A.C.

1995-07-01

Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 famlies with triple A syndrome. The proband with IGD was a homozygote for an A {r_arrow}G substitution, changing tyrosine 254 to cysteine in the third extracellular loopmore » of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome. 19 refs., 1 fig.« less
Passenger mutations and aberrant gene expression in congenic tissue plasminogen activator-deficient mouse strains.

PubMed

Szabo, R; Samson, A L; Lawrence, D A; Medcalf, R L; Bugge, T H

2016-08-01

Essentials C57BL/6J-tissue plasminogen activator (tPA)-deficient mice are widely used to study tPA function. Congenic C57BL/6J-tPA-deficient mice harbor large 129-derived chromosomal segments. The 129-derived chromosomal segments contain gene mutations that may confound data interpretation. Passenger mutation-free isogenic tPA-deficient mice were generated for study of tPA function. Background The ability to generate defined null mutations in mice revolutionized the analysis of gene function in mammals. However, gene-deficient mice generated by using 129-derived embryonic stem cells may carry large segments of 129 DNA, even when extensively backcrossed to reference strains, such as C57BL/6J, and this may confound interpretation of experiments performed in these mice. Tissue plasminogen activator (tPA), encoded by the PLAT gene, is a fibrinolytic serine protease that is widely expressed in the brain. A number of neurological abnormalities have been reported in tPA-deficient mice. Objectives To study genetic contamination of tPA-deficient mice. Materials and methods Whole genome expression array analysis, RNAseq expression profiling, low- and high-density single nucleotide polymorphism (SNP) analysis, bioinformatics and genome editing were used to analyze gene expression in tPA-deficient mouse brains. Results and conclusions Genes differentially expressed in the brain of Plat(-/-) mice from two independent colonies highly backcrossed onto the C57BL/6J strain clustered near Plat on chromosome 8. SNP analysis attributed this anomaly to about 20 Mbp of DNA flanking Plat being of 129 origin in both strains. Bioinformatic analysis of these 129-derived chromosomal segments identified a significant number of mutations in genes co-segregating with the targeted Plat allele, including several potential null mutations. Using zinc finger nuclease technology, we generated novel 'passenger mutation'-free isogenic C57BL/6J-Plat(-/-) and FVB/NJ-Plat(-/-) mouse strains by introducing an 11 bp deletion into the exon encoding the signal peptide. These novel mouse strains will be a useful community resource for further exploration of tPA function in physiological and pathological processes. © 2016 International Society on Thrombosis and Haemostasis.
Application of wide selected-ion monitoring data-independent acquisition to identify tomato fruit proteins regulated by the CUTIN DEFICIENT2 transcription factor

USDA-ARS?s Scientific Manuscript database

We describe here the use of label-free wide selected-ion monitoring data-independent acquisition (WiSIM-DIA) to identify proteins that are involved in the formation of tomato (Solanum lycopersicum) fruit cuticles and that are regulated by the transcription factor CUTIN DEFICIENT2 (CD2). A spectral l...
Increasing quality of life in pulmonary arterial hypertension: is there a role for nutrition?

PubMed

Vinke, Paulien; Jansen, Suzanne M; Witkamp, Renger F; van Norren, Klaske

2018-06-16

Pulmonary arterial hypertension (PAH) is a progressive disease primarily affecting the pulmonary vasculature and heart. PAH patients suffer from exercise intolerance and fatigue, negatively affecting their quality of life. This review summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Pubmed/Medline, Scopus, and Web of Science were searched for publications on pathophysiological mechanisms of PAH negatively affecting physical activity potential and nutritional status, and for potential effects of interventions involving exercise or nutritional measures known to improve exercise intolerance. Pathophysiological processes that contribute to exercise intolerance and impaired quality of life of PAH patients include right ventricular dysfunction, inflammation, skeletal muscle alterations, and dysfunctional energy metabolism. PAH-related nutritional deficiencies and metabolic alterations have been linked to fatigue, exercise intolerance, and endothelial dysfunction. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.
Nitric oxide maintains cell survival of Trichomonas vaginalis upon iron depletion.

PubMed

Cheng, Wei-Hung; Huang, Kuo-Yang; Huang, Po-Jung; Hsu, Jo-Hsuan; Fang, Yi-Kai; Chiu, Cheng-Hsun; Tang, Petrus

2015-07-25

Iron plays a pivotal role in the pathogenesis of Trichomonas vaginalis, the causative agent of highly prevalent human trichomoniasis. T. vaginalis resides in the vaginal region, where the iron concentration is constantly changing. Hence, T. vaginalis must adapt to variations in iron availability to establish and maintain an infection. The free radical signaling molecules reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been proven to participate in iron deficiency in eukaryotes. However, little is known about the roles of these molecules in iron-deficient T. vaginalis. T. vaginalis cultured in iron-rich and -deficient conditions were collected for all experiments in this study. Next generation RNA sequencing was conducted to investigate the impact of iron on transcriptome of T. vaginalis. The cell viabilities were monitored after the trophozoites treated with the inhibitors of nitric oxide (NO) synthase (L-NG-monomethyl arginine, L-NMMA) and proteasome (MG132). Hydrogenosomal membrane potential was measured using JC-1 staining. We demonstrated that NO rather than ROS accumulates in iron-deficient T. vaginalis. The level of NO was blocked by MG132 and L-NMMA, indicating that NO production is through a proteasome and arginine dependent pathway. We found that the inhibition of proteasome activity shortened the survival of iron-deficient cells compared with untreated iron-deficient cells. Surprisingly, the addition of arginine restored both NO level and the survival of proteasome-inhibited cells, suggesting that proteasome-derived NO is crucial for cell survival under iron-limited conditions. Additionally, NO maintains the hydrogenosomal membrane potential, a determinant for cell survival, emphasizing the cytoprotective effect of NO on iron-deficient T. vaginalis. Collectively, we determined that NO produced by the proteasome prolonged the survival of iron-deficient T. vaginalis via maintenance of the hydrogenosomal functions. The findings in this study provide a novel role of NO in adaptation to iron-deficient stress in T. vaginalis and shed light on a potential therapeutic strategy for trichomoniasis.
The effect of ingested sulfite on visual evoked potentials, lipid peroxidation, and antioxidant status of brain in normal and sulfite oxidase-deficient aged rats.

PubMed

Ozsoy, Ozlem; Aras, Sinem; Ozkan, Ayse; Parlak, Hande; Aslan, Mutay; Yargicoglu, Piraye; Agar, Aysel

2016-07-01

Sulfite, commonly used as a preservative in foods, beverages, and pharmaceuticals, is a very reactive and potentially toxic molecule which is detoxified by sulfite oxidase (SOX). Changes induced by aging may be exacerbated by exogenous chemicals like sulfite. The aim of this study was to investigate the effects of ingested sulfite on visual evoked potentials (VEPs) and brain antioxidant statuses by measuring superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. Brain lipid oxidation status was also determined via thiobarbituric acid reactive substances (TBARS) in normal- and SOX-deficient aged rats. Rats do not mimic the sulfite responses seen in humans because of their relatively high SOX activity level. Therefore this study used SOX-deficient rats since they are more appropriate models for studying sulfite toxicity. Forty male Wistar rats aged 24 months were randomly assigned to four groups: control (C), sulfite (S), SOX-deficient (D) and SOX-deficient + sulfite (DS). SOX deficiency was established by feeding rats with low molybdenum (Mo) diet and adding 200 ppm tungsten (W) to their drinking water. Sulfite in the form of sodium metabisulfite (25 mg kg(-1) day(-1)) was given by gavage. Treatment continued for 6 weeks. At the end of the experimental period, flash VEPs were recorded. Hepatic SOX activity was measured to confirm SOX deficiency. SOX-deficient rats had an approximately 10-fold decrease in hepatic SOX activity compared with the normal rats. The activity of SOX in deficient rats was thus in the range of humans. There was no significant difference between control and treated groups in either latence or amplitude of VEP components. Brain SOD, CAT, and GPx activities and brain TBARS levels were similar in all experimental groups compared with the control group. Our results indicate that exogenous administration of sulfite does not affect VEP components and the antioxidant/oxidant status of aged rat brains. © The Author(s) 2014.
Urine metabonomic profiling of a female adolescent with PIT-1 mutation before and during growth hormone therapy: insights into the metabolic effects of growth hormone.

PubMed

Abd Rahman, Shaffinaz; Schirra, Horst Joachim; Lichanska, Agnieszka M; Huynh, Tony; Leong, Gary M

2013-01-01

Growth hormone (GH) is a protein hormone with important roles in growth and metabolism. The objective of this study was to investigate the metabolism of a human subject with severe GH deficiency (GHD) due to a PIT-1 gene mutation and the metabolic effects of GH therapy using Nuclear Magnetic Resonance (NMR)-based metabonomics. NMR-based metabonomics is a platform that allows the metabolic profile of biological fluids such as urine to be recorded, and any alterations in the profile modulated by GH can potentially be detected. Urine samples were collected from a female subject with severe GHD before, during and after GH therapy, and from healthy age- and sex-matched controls and analysed with NMR-based metabonomics. The samples were collected at a hospital and the study was performed at a research facility. We studied a 17 year old female adolescent with severe GHD secondary to PIT-1 gene mutation who had reached final adult height and who had ceased GH therapy for over 3 years. The subject was subsequently followed for 5 years with and without GH therapy. Twelve healthy age-matched female subjects acted as control subjects. The GH-deficient subject re-commenced GH therapy at a dose of 1 mg/day to normalise serum IGF-1 levels. Urine metabolic profiles were recorded using NMR spectroscopy and analysed with multivariate statistics to distinguish the profiles at different time points and identify significant metabolites affected by GH therapy. NMR-based metabonomics revealed that the metabolic profile of the GH-deficient subject altered with GH therapy and that her profile was different from healthy controls before, and during withdrawal of GH therapy. This study illustrates the potential use of NMR-based metabonomics for monitoring the effects of GH therapy on metabolism by profiling the urine of GH-deficient subjects. Further controlled studies in larger numbers of GH-deficient subjects are required to determine the clinical benefits of NMR-based metabonomics in subjects receiving GH therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.
Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.

PubMed

Cappuccio, Gerarda; Pinelli, Michele; Alagia, Marianna; Donti, Taraka; Day-Salvatore, Debra-Lynn; Veggiotti, Pierangelo; De Giorgis, Valentina; Lunghi, Simona; Vari, Maria Stella; Striano, Pasquale; Brunetti-Pierri, Nicola; Kennedy, Adam D; Elsea, Sarah H

2017-01-01

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.
Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

PubMed Central

Cappuccio, Gerarda; Pinelli, Michele; Alagia, Marianna; Donti, Taraka; Day-Salvatore, Debra-Lynn; Veggiotti, Pierangelo; De Giorgis, Valentina; Lunghi, Simona; Vari, Maria Stella; Striano, Pasquale; Brunetti-Pierri, Nicola; Kennedy, Adam D.

2017-01-01

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation. PMID:28961260
Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

PubMed

Mignon-Ravix, Cécile; Cacciagli, Pierre; Choucair, Nancy; Popovici, Cornel; Missirian, Chantal; Milh, Mathieu; Mégarbané, André; Busa, Tiffany; Julia, Sophie; Girard, Nadine; Badens, Catherine; Sigaudy, Sabine; Philip, Nicole; Villard, Laurent

2014-08-01

High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed. © 2014 Wiley Periodicals, Inc.
Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

PubMed

Taylor, Robert W; Pyle, Angela; Griffin, Helen; Blakely, Emma L; Duff, Jennifer; He, Langping; Smertenko, Tania; Alston, Charlotte L; Neeve, Vivienne C; Best, Andrew; Yarham, John W; Kirschner, Janbernd; Schara, Ulrike; Talim, Beril; Topaloglu, Haluk; Baric, Ivo; Holinski-Feder, Elke; Abicht, Angela; Czermin, Birgit; Kleinle, Stephanie; Morris, Andrew A M; Vassallo, Grace; Gorman, Grainne S; Ramesh, Venkateswaran; Turnbull, Douglass M; Santibanez-Koref, Mauro; McFarland, Robert; Horvath, Rita; Chinnery, Patrick F

2014-07-02

Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease. To determine the molecular basis of multiple respiratory chain complex deficiencies. We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family. Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MTO1. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%). Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.
Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome.

PubMed

Cariboni, Anna; André, Valentina; Chauvet, Sophie; Cassatella, Daniele; Davidson, Kathryn; Caramello, Alessia; Fantin, Alessandro; Bouloux, Pierre; Mann, Fanny; Ruhrberg, Christiana

2015-06-01

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.
ARID1B is a specific vulnerability in ARID1A-mutant cancers

PubMed Central

Helming, Katherine C.; Wang, Xiaofeng; Wilson, Boris G.; Vazquez, Francisca; Haswell, Jeffrey R.; Manchester, Haley E.; Kim, Youngha; Kryukov, Gregory V.; Ghandi, Mahmoud; Aguirre, Andrew J.; Jagani, Zainab; Wang, Zhong; Garraway, Levi A.; Hahn, William C.; Roberts, Charles W. M.

2014-01-01

Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers. PMID:24562383
New mutations affecting induced mutagenesis in yeast.

PubMed

Lawrence, C W; Krauss, B R; Christensen, R B

1985-01-01

Previously isolated mutations in baker's yeast, Saccharomyces cerevisiae, that impair induced mutagenesis were all identified with the aid of tests that either exclusively or predominantly detect base-pair substitutions. To avoid this bias, we have screened 11 366 potentially mutant clones for UV-induced reversion of the frameshift allele, his4-38, and have identified 10 mutants that give much reduced yields of revertants. Complementation and recombination tests show that 6 of these carry mutations at the previously known REV1, REV1 and REV3 loci, while the remaining 4 define 3 new genes, REV4 (2 mutations), REV5 and REV6. The rev4 mutations are readily suppressed in many genetic backgrounds and, like the rev5 mutation, impart only a limited deficiency for induced mutagenesis: it is likely, therefore that the REV4+ and REV5+ gene functions are only remotely concerned with this process. The rev6 mutants have a more general deficiency, however, as well as marked sensitivity to UV and an increased spontaneous mutation rate, properties that suggest the REV6 gene is directly involved in mutation induction. The REV5 gene is located about 1 cM proximal to CYC1 on chromosome X.
The mechanisms of low nitrogen induced weakened photosynthesis in summer maize (Zea mays L.) under field conditions.

PubMed

Wei, Shanshan; Wang, Xiangyu; Shi, Deyang; Li, Yanhong; Zhang, Jiwang; Liu, Peng; Zhao, Bin; Dong, Shuting

2016-08-01

Soil nitrogen (N) shortage is a problem which affects many developing nations. Crops grown with low soil N levels show a marked decrease in the rate of photosynthesis and this deficiency reduces crop yield significantly. Therefore, developing a better understanding of the mechanisms by which low N levels cause decreased photosynthesis is crucial for maize agriculture. To better understand this process, we assessed the responses of photosynthesis traits and enzymatic activities in the summer maize cultivar Denghai 618 under field conditions with and without the use of N fertilisers. We measured photosynthesis parameters, and compared proteome compositions to identify the mechanisms of physiological and biochemical adaptations to N deficiency in maize. We observed that parameters that indicated the rate of photosynthesis decreased significantly under N deficiency, and this response was associated with leaf senescence. Moreover, we identified 37 proteins involved in leaf photosynthesis, and found that N deficiency significantly affected light-dependent and light-independent reactions in maize leaf photosynthesis. Although further analysis is required to fully elucidate the roles of these proteins in the response to N deficiency, our study identified candidate proteins which may be involved in the regulatory mechanisms involved in reduced photosynthesis under low N conditions in maize. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Recognition of simulated cyanosis by color-vision-normal and color-vision-deficient subjects.

PubMed

Dain, Stephen J

2014-04-01

There are anecdotal reports that the recognition of cyanosis is difficult for some color-deficient observers. The chromaticity changes of blood with oxygenation in vitro lie close to the dichromatic confusion lines. The chromaticity changes of lips and nail beds measured in vivo are also generally aligned in the same way. Experiments involving visual assessment of cyanosis in vivo are fraught with technical and ethical difficulties A single lower face image of a healthy individual was digitally altered to produce levels of simulated cyanosis. The color change is essentially one of saturation. Some images with other color changes were also included to ensure that there was no propensity to identify those as cyanosed. The images were assessed for reality by a panel of four instructors from the NSW Ambulance Service training section. The images were displayed singly and the observer was required to identify if the person was cyanosed or not. Color normal subjects comprised 32 experienced ambulance officers and 27 new recruits. Twenty-seven color deficient subjects (non-NSW Ambulance Service) were examined. The recruits were less accurate and slower at identifying the cyanosed images and the color vision deficient were less accurate and slower still. The identification of cyanosis is a skill that improves with training and is adversely affected in color deficient observers.
Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency.

PubMed

Gruntman, Alisha M; Flotte, Terence R

2017-01-01

This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

Potassium, magnesium, and calcium deficiency symptoms

Treesearch

Edward I. Sucoff

1961-01-01

A loblolly pine or Virginia pine tree that shows visible symptoms of nutrient deficiency is sick. This means that the life processes of the tree are malfunctioning and that, among other things, the growth rate is probably less than normal, and the life of the tree may be threatened. However, if the deficiency can be identified, treatment with the proper fertilizer may...
Are MAO-A deficiency states in the general population and in putative high-risk populations highly uncommon?

PubMed

Murphy, D L; Sims, K; Eisenhofer, G; Greenberg, B D; George, T; Berlin, F; Zametkin, A; Ernst, M; Breakefield, X O

1998-01-01

Lack of monoamine oxidase A (MAO-A) due to either Xp chromosomal deletions or alterations in the coding sequence of the gene for this enzyme are associated with marked changes in monoamine metabolism and appear to be associated with variable cognitive deficits and behavioral changes in humans and in transgenic mice. In mice, some of the most marked behavioral changes are ameliorated by pharmacologically-induced reductions in serotonin synthesis during early development, raising the question of possible therapeutic interventions in humans with MAO deficiency states. At the present time, only one multi-generational family and a few other individuals with marked MAO-A deficiency states have been identified and studied in detail. Although MAO deficiency states associated with Xp chromosomal deletions were identified by distinct symptoms (including blindness in infancy) produced by the contiguous Norrie disease gene, the primarily behavioral phenotype of individuals with the MAO mutation is less obvious. This paper reports a sequential research design and preliminary results from screening several hundred volunteers in the general population and from putative high-risk groups for possible MAO deficiency states. These preliminary results suggest that marked MAO deficiency states are very rare.
YouScript IMPACT Registry

ClinicalTrials.gov

2017-02-27

Adverse Drug Events; Adverse Drug Reactions; Drug Interaction Potentiation; Drug Metabolism, Poor, CYP2D6-RELATED; Drug Metabolism, Poor, CYP2C19-RELATED; Cytochrome P450 Enzyme Deficiency; Cytochrome P450 CYP2D6 Enzyme Deficiency; Cytochrome P450 CYP2C9 Enzyme Deficiency; Cytochrome P450 CYP2C19 Enzyme Deficiency; Cytochrome P450 CYP3A Enzyme Deficiency; Poor Metabolizer Due to Cytochrome P450 CYP2C9 Variant; Poor Metabolizer Due to Cytochrome P450 CYP2C19 Variant; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Pharmacogenetic Testing Among Home Health Patients

ClinicalTrials.gov

2016-09-20

Adverse Drug Events; Adverse Drug Reactions; Drug Interaction Potentiation; Drug Metabolism, Poor, CYP2D6-RELATED; Drug Metabolism, Poor, CYP2C19-RELATED; Cytochrome P450 Enzyme Deficiency; Cytochrome P450 CYP2D6 Enzyme Deficiency; Cytochrome P450 CYP2C9 Enzyme Deficiency; Cytochrome P450 CYP2C19 Enzyme Deficiency; Cytochrome P450 CYP3A Enzyme Deficiency; Poor Metabolizer Due to Cytochrome P450 CYP2C9 Variant; Poor Metabolizer Due to Cytochrome p450 CYP2C19 Variant; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant
Pyruvate Kinase Deficiency in Sub-Saharan Africa: Identification of a Highly Frequent Missense Mutation (G829A;Glu277Lys) and Association with Malaria

PubMed Central

Machado, Patrícia; Manco, Licínio; Gomes, Cláudia; Mendes, Cristina; Fernandes, Natércia; Salomé, Graça; Sitoe, Luis; Chibute, Sérgio; Langa, José; Ribeiro, Letícia; Miranda, Juliana; Cano, Jorge; Pinto, João; Amorim, António; do Rosário, Virgílio E.; Arez, Ana Paula

2012-01-01

Background Pyruvate kinase (PK) deficiency, causing hemolytic anemia, has been associated to malaria protection and its prevalence in sub-Saharan Africa is not known so far. This work shows the results of a study undertaken to determine PK deficiency occurrence in some sub-Saharan African countries, as well as finding a prevalent PK variant underlying this deficiency. Materials and Methods Blood samples of individuals from four malaria endemic countries (Mozambique, Angola, Equatorial Guinea and Sao Tome and Principe) were analyzed in order to determine PK deficiency occurrence and detect any possible high frequent PK variant mutation. The association between this mutation and malaria was ascertained through association studies involving sample groups from individuals showing different malaria infection and outcome status. Results The percentage of individuals showing a reduced PK activity in Maputo was 4.1% and the missense mutation G829A (Glu277Lys) in the PKLR gene (only identified in three individuals worldwide to date) was identified in a high frequency. Heterozygous carrier frequency was between 6.7% and 2.6%. A significant association was not detected between either PK reduced activity or allele 829A frequency and malaria infection and outcome, although the variant was more frequent among individuals with uncomplicated malaria. Conclusions This was the first study on the occurrence of PK deficiency in several areas of Africa. A common PKLR mutation G829A (Glu277Lys) was identified. A global geographical co-distribution between malaria and high frequency of PK deficiency seems to occur suggesting that malaria may be a selective force raising the frequency of this 277Lys variant. PMID:23082140
[Impedance characteristics of ear acupoints in identifying excess or deficiency syndrome of stroke].

PubMed

Wang, Pin; Yang, Hua-Yuan; Wang, Yi-Qin

2010-06-01

To explore the impedance characteristics of ear acupoints in stroke patients with excess or deficiency syndrome, and to provide basis data for objective study of the syndromes of stroke. The data of electrical characteristics of ear acupoints in stroke patients and healthy people were collected, and excess syndrome and deficiency syndrome of stroke were identified by quantifying the syndromes of stroke using scales. The differences in impedance characteristics of ear acupoints between stroke patients and healthy people were analyzed, and the differences in impedance characteristics of ear acupoints between stroke patients with excess syndrome and stroke patients with deficiency syndrome were analyzed too. The correlation among impedance characteristics of ear acupoints, stroke and the syndromes was also analyzed. There were significant differences in impedance characteristics of ear acupoints between stroke patients and healthy people (P<0.05,P<0.01). The ear acupoints CO12 (Gan) and CO13 (Pi) had a significant role in diagnosing stroke as compared with CO18 (Neifenmi), AT3.4.AH12i (Naogan), CO10 (Shen), TG2p (Shenshangxian), AH6a (Jiaogan), AT4 (Pizhixia), and CO15 (Xin). There were significant differences in impedance characteristics of ear acupoints between stroke patients with excess syndrome and stroke patients with deficiency syndrome (P<0.05, P<0.01). The ear acupoints AH6a (Jiaogan) and CO10 (Shen) played an important role in differentiation diagnosis of excess syndrome and deficiency syndrome of stroke, followed by CO18 (Neifenmi), TF4 (Shenmen) and TG2p (Shenshangxian). Some ear acupoints with diagnostic value for stroke may provide basis of objective research for stroke diagnosis as well as identifying excess syndrome and deficiency syndrome of stroke.
Chemical Structure and Morphology of Dorsal Root Ganglion Neurons from Naive and Inflamed Mice*

PubMed Central

Barabas, Marie E.; Mattson, Eric C.; Aboualizadeh, Ebrahim; Hirschmugl, Carol J.; Stucky, Cheryl L.

2014-01-01

Fourier transform infrared spectromicroscopy provides label-free imaging to detect the spatial distribution of the characteristic functional groups in proteins, lipids, phosphates, and carbohydrates simultaneously in individual DRG neurons. We have identified ring-shaped distributions of lipid and/or carbohydrate enrichment in subpopulations of neurons which has never before been reported. These distributions are ring-shaped within the cytoplasm and are likely representative of the endoplasmic reticulum. The prevalence of chemical ring subtypes differs between large- and small-diameter neurons. Peripheral inflammation increased the relative lipid content specifically in small-diameter neurons, many of which are nociceptive. Because many small-diameter neurons express an ion channel involved in inflammatory pain, transient receptor potential ankyrin 1 (TRPA1), we asked whether this increase in lipid content occurs in TRPA1-deficient (knock-out) neurons. No statistically significant change in lipid content occurred in TRPA1-deficient neurons, indicating that the inflammation-mediated increase in lipid content is largely dependent on TRPA1. Because TRPA1 is known to mediate mechanical and cold sensitization that accompanies peripheral inflammation, our findings may have important implications for a potential role of lipids in inflammatory pain. PMID:25271163
Development of SH2 probes and pull-down assays to detect pathogen-induced, site-specific tyrosine phosphorylation of the TLR adaptor SCIMP.

PubMed

Luo, Lin; Tong, Samuel J; Wall, Adam A; Khromykh, Tatiana; Sweet, Matthew J; Stow, Jennifer L

2017-07-01

Protein tyrosine phosphorylation guides many molecular interactions for cellular functions. SCIMP is a transmembrane adaptor protein (TRAP) family member that mediates selective proinflammatory cytokine responses generated by pathogen-activated Toll-like receptor (TLR) pathways in macrophages. TLR activation triggers SCIMP phosphorylation and selective phosphorylation of distinct tyrosine residues on this adaptor offers the potential for regulating or biasing inflammatory responses. To analyze site-specific phosphorylation events, we developed three probes based on the SH2 domains of known SCIMP effectors, and used them for pull-downs from macrophage extracts. CRISPR-mediated SCIMP-deficient RAW264.7 macrophage-like cells were reconstituted with various phosphorylation-deficient (Y58F, Y96F, Y120F) SCIMPs, and used to demonstrate the specificity of LPS/TLR4-induced, site-specific phosphorylation of SCIMP for the temporal recruitment of the effectors Grb2, Csk and SLP65. Our findings reveal potential for differential SCIMP phosphorylation and specific effectors to influence TLR signaling and inflammatory programs. Furthermore, the use of Csk-SH2 pull-downs to identify additional known and new Csk targets in LPS-activated macrophages reveals the wider utility of our SH2 probes.
Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus

PubMed Central

English, Jane A.; Harauma, Akiko; Föcking, Melanie; Wynne, Kieran; Scaife, Caitriona; Cagney, Gerard; Moriguchi, Toru; Cotter, David R.

2013-01-01

Omega-3 fatty acid (n-3 FA) deficiency is an environmental risk factor for schizophrenia, yet characterization of the consequences of deficiency at the protein level in the brain is limited. We aimed to identify the protein pathways disrupted as a consequence of chronic n-3 deficiency in the hippocampus of mice. Fatty acid analysis of the hippocampus following chronic dietary deficiency revealed a 3-fold decrease (p < 0.001) in n-3 FA levels. Label free LC-MS/MS analysis identified and profiled 1008 proteins, of which 114 were observed to be differentially expressed between n-3 deficient and control groups (n = 8 per group). The cellular processes that were most implicated were neuritogenesis, endocytosis, and exocytosis, while specific protein pathways that were most significantly dysregulated were mitochondrial dysfunction and clathrin mediated endocytosis (CME). In order to characterize whether these processes and pathways are ones influenced by antipsychotic medication, we used LC-MS/MS to test the differential expression of these 114 proteins in the hippocampus of mice chronically treated with the antipsychotic agent haloperidol. We observed 23 of the 114 proteins to be differentially expressed, 17 of which were altered in the opposite direction to that observed following n-3 deficiency. Overall, our findings point to disturbed synaptic function, neuritogenesis, and mitochondrial function as a consequence of dietary deficiency in n-3 FA. This study greatly aids our understanding of the molecular mechanism by which n-3 deficiency impairs normal brain function, and provides clues as to how n-3 FA exert their therapeutic effect in early psychosis. PMID:24194745
Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation

PubMed Central

Wong, Carmen P.; Rinaldi, Nicole A.; Ho, Emily

2015-01-01

Scope Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. Methods and results An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency up-regulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, that coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Conclusion Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation. PMID:25656040
Complex pattern of immune evasion in MSI colorectal cancer.

PubMed

Ozcan, Mine; Janikovits, Jonas; von Knebel Doeberitz, Magnus; Kloor, Matthias

2018-01-01

Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.
Utilization of the Seniors Falls Investigation Methodology to identify system-wide causes of falls in community-dwelling seniors.

PubMed

Zecevic, Aleksandra A; Salmoni, Alan W; Lewko, John H; Vandervoort, Anthoney A; Speechley, Mark

2009-10-01

As a highly heterogeneous group, seniors live in complex environments influenced by multiple physical and social structures that affect their safety. Until now, the major approach to falls research has been person centered. However, in industrial settings, the individuals involved in an accident are seen as the inheritors of system defects. The objective of the present study was to investigate safety deficiencies that contributed to falls in community-dwelling seniors using a systems approach. The investigations were conducted using the Seniors Falls Investigation Methodology (SFIM), an adapted version of a method used to examine transportation accidents, such as airplane crashes. Fifteen seniors, who experienced a fall or near fall, participated in multiple case studies. A cross-case synthesis was used to summarize findings and identify common patterns of causes and safety deficiencies. Falls and near falls are a result of latent unsafe conditions, and unsafe acts and decisions combined in a diverse set of circumstances. If not identified and removed, these unsafe conditions can cause falls for other seniors. This study provided compelling evidence that causes of falling are systemic and develop over time. It demonstrated that the systems approach is needed to expand the focus from the individual to multilayered organizational and supervisory causes. The SFIM demonstrated capability to identify causes of falls that will allow better prevention and management programs, hence advancing seniors' safety. SFIM shows great potential for implementation in organized settings, such as hospitals and long-term care homes.
Prevalence of vitamin D deficiency and associated factors in women and newborns in the immediate postpartum period

PubMed Central

do Prado, Mara Rúbia Maciel Cardoso; Oliveira, Fabiana de Cássia Carvalho; Assis, Karine Franklin; Ribeiro, Sarah Aparecida Vieira; do Prado, Pedro Paulo; Sant'Ana, Luciana Ferreira da Rocha; Priore, Silvia Eloiza; Franceschini, Sylvia do Carmo Castro

2015-01-01

Abstract Objective: To assess the prevalence of vitamin D deficiency and its associated factors in women and their newborns in the postpartum period. Methods: This cross-sectional study evaluated vitamin D deficiency/insufficiency in 226 women and their newborns in Viçosa (Minas Gerais, BR) between December 2011 and November 2012. Cord blood and venous maternal blood were collected to evaluate the following biochemical parameters: vitamin D, alkaline phosphatase, calcium, phosphorus and parathyroid hormone. Poisson regression analysis, with a confidence interval of 95%, was applied to assess vitamin D deficiency and its associated factors. Multiple linear regression analysis was performed to identify factors associated with 25(OH)D deficiency in the newborns and women from the study. The criteria for variable inclusion in the multiple linear regression model was the association with the dependent variable in the simple linear regression analysis, considering p<0.20. Significance level was α <5%. Results: From 226 women included, 200 (88.5%) were 20-44 years old; the median age was 28 years. Deficient/insufficient levels of vitamin D were found in 192 (85%) women and in 182 (80.5%) neonates. The maternal 25(OH)D and alkaline phosphatase levels were independently associated with vitamin D deficiency in infants. Conclusions: This study identified a high prevalence of vitamin D deficiency and insufficiency in women and newborns and the association between maternal nutritional status of vitamin D and their infants' vitamin D status. PMID:26100593
Luteal phase deficiency. An underdiagnosed and overtreated reproductive endocrine disorder.

PubMed

Soules, M R

1987-12-01

Although luteal phase deficiency is rather time consuming, expensive, and sometimes painful to diagnose and treat, this disease entity is associated with a high degree of treatment success. Physicians are encouraged to become more aware of luteal phase deficiency as a potential diagnosis in the infertile woman. If the recommendations are followed in the diagnosis and treatment of luteal phase deficiency, a high degree of success can be achieved in infertile couples who otherwise would be diagnosed as having idiopathic infertility (and be ineffectively treated).
Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study.

PubMed

Wheeler, Benjamin J; Dickson, Nigel P; Houghton, Lisa A; Ward, Leanne M; Taylor, Barry J

2015-08-01

To investigate the incidence and characteristics of vitamin D deficiency rickets in New Zealand (NZ). Prospective surveillance among paediatricians of Vitamin D Deficiency Rickets was conducted by the New Zealand Paediatric Surveillance Unit (NZPSU) for 36 months, from July 2010 to June 2013, inclusive. Inclusion criteria were: children and adolescents <15 years of age with vitamin D deficiency rickets (defined by low serum 25-hydroxyvitamin D and elevated alkaline phosphatase levels, and/or radiological rickets). Fifty-eight children with confirmed vitamin D deficiency rickets were identified. Median age was 1.4 (range 0.3-11) years, 47% were male, and 95% of the children were born in NZ; however, the majority of the mothers (68%) were born outside NZ. Overall annual incidence of rickets in children aged <15 years was 2.2/100,000 (95%CI 1.4-3.5); with incidence in those <3 years being 10.5/100,000 (95%CI 6.7-16.6). Skeletal abnormalities, poor growth and motor delay were the most common presenting features, with hypocalcaemic convulsion in 16% of children. Key risk factors identified were: darker skin pigment, Indian and African ethnicity, age <3 years, exclusive breast feeding, and southern latitude, particularly when combined with season (winter/spring). Of the patients reported, none had received appropriate vitamin D supplementation. Vitamin D deficiency rickets remains a problem for NZ children. Key risk factors remain similar to those identified in the international literature. Preventative targeted vitamin D supplementation, as per existing national guidelines, was lacking in all cases reported. Vitamin D deficiency rickets is the most significant manifestation of vitamin D deficiency in growing children. To reduce the incidence of this disease among those at high risk, increasing awareness and implementation of current public health policies for targeted maternal, infant and child supplementation are required. © 2015 Public Health Association of Australia.
Factors Associated with Vitamin D Testing, Deficiency, Intake, and Supplementation in Patients with Chronic Pain.

PubMed

Gaikwad, Manasi; Vanlint, Simon; Moseley, G Lorimer; Mittinty, Murthy N; Stocks, Nigel

2017-11-02

Vitamin D deficiency is a public health issue, with reports of six- to twenty-five-fold rise in vitamin D testing. Vitamin D deficiency has been linked to many chronic diseases such as diabetes mellitus, cardiovascular disease, depression, and chronic pain. Identifying factors associated with risk of deficiency in individuals with chronic pain will help minimize time and cost. This study aims to examine the factors associated with vitamin D testing, intake, and physician-advised supplementation in individuals with chronic pain. Using a cross-sectional design, data were collected from 465 individuals with chronic pain. These data were analyzed using penalized logistic regression with the LASSO technique. Fifty-seven percent reported being tested for vitamin D, about 40% reported being diagnosed with vitamin D deficiency, and of those who had been tested, 60% reported taking vitamin D supplementation. The findings suggest older age (OR 3.12, CI [1.02, 9.50]) and higher mean pain intensity score (OR 2.02, CI [1.13, 3.59]) increased an individual's chance of being vitamin D deficient. Unemployment or on leave due to pain (OR 1.79, [CI 1.03, 3.11]), part-time employment (OR 1.86, CI [1.02, 3.39]), and being a resident of Australia (OR 2.32, CI [1.13, 4.72]) increased chances of being tested for vitamin D. Being diagnosed with vitamin D deficiency (OR 6.67, CI [2.75, 16.19]), unemployed or on leave due to pain (OR 3.71, CI [1.25, 11.00]), and in part-time employment (OR 2.69, CI [0.86, 8.38]) were associated with physician-advised vitamin D supplementation. Our results may have practical implications, as identifying pretest risk factors may assist in identifying who is at risk of vitamin D deficiency, whom to test, and when to treat.
Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development.

PubMed

Schachtschneider, Kyle M; Liu, Yingkai; Rund, Laurie A; Madsen, Ole; Johnson, Rodney W; Groenen, Martien A M; Schook, Lawrence B

2016-11-03

Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency. In total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function. Neonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive development in humans.
Vision based nutrient deficiency classification in maize plants using multi class support vector machines

NASA Astrophysics Data System (ADS)

Leena, N.; Saju, K. K.

2018-04-01

Nutritional deficiencies in plants are a major concern for farmers as it affects productivity and thus profit. The work aims to classify nutritional deficiencies in maize plant in a non-destructive mannerusing image processing and machine learning techniques. The colored images of the leaves are analyzed and classified with multi-class support vector machine (SVM) method. Several images of maize leaves with known deficiencies like nitrogen, phosphorous and potassium (NPK) are used to train the SVM classifier prior to the classification of test images. The results show that the method was able to classify and identify nutritional deficiencies.
Primary and secondary CoQ(10) deficiencies in humans.

PubMed

Quinzii, Catarina M; Hirano, Michio

2011-01-01

CoQ(10) deficiencies are clinically and genetically heterogeneous. This syndrome has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis variably contribute to the pathogenesis of primary CoQ(10) deficiencies. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.
Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice

PubMed Central

Uz, Tolga; Dimitrijevic, Nikola; Imbesi, Marta; Manev, Hari; Manev, Radmila

2008-01-01

A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX; 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment. In this work, we evaluated the behavioral effects of MK-886 in an automated assay of mouse forced swimming, which identifies antidepressant activity as increased climbing behavior and/or decreased rest time. Whereas a single injection of MK-886 (3 and 10 mg/kg) did not affect forced swimming behaviors assayed 30 min later, 6 daily injections of 3 mg/kg MK-886 slightly increased climbing and significantly reduced rest time in wild-type mice but not in 5-LOX-deficient mice. A diet delivery of MK-886, 4 μg per 100 mg body-weight per day, required three weeks to affect forced swimming; it increased climbing behavior. Climbing behavior was also increased in naive 5-LOX-deficient mice compared to naive wild-type controls. These results suggest that 5-LOX inhibition and deficiency may be associated with antidepressant activity. Increased climbing in a forced swimming assay is a typical outcome of antidepressants that increase noradrenergic and dopaminergic activity. Interestingly, 5-LOX deficiency and MK-886 treatment have been shown to be capable of increasing the behavioral effects of a noradrenaline/dopamine-potentiating drug, cocaine. Future research is needed to evaluate the clinical relevance of our findings. PMID:18403121

DNA double-strand break repair of blood lymphocytes and normal tissues analysed in a preclinical mouse model: implications for radiosensitivity testing.

PubMed

Rübe, Claudia E; Grudzenski, Saskia; Kühne, Martin; Dong, Xiaorong; Rief, Nicole; Löbrich, Markus; Rübe, Christian

2008-10-15

Radiotherapy is an effective cancer treatment, but a few patients suffer severe radiation toxicities in neighboring normal tissues. There is increasing evidence that the variable susceptibility to radiation toxicities is caused by the individual genetic predisposition, by subtle mutations, or polymorphisms in genes involved in cellular responses to ionizing radiation. Double-strand breaks (DSB) are the most deleterious form of radiation-induced DNA damage, and DSB repair deficiencies lead to pronounced radiosensitivity. Using a preclinical mouse model, the highly sensitive gammaH2AX-foci approach was tested to verify even subtle, genetically determined DSB repair deficiencies known to be associated with increased normal tissue radiosensitivity. By enumerating gammaH2AX-foci in blood lymphocytes and normal tissues (brain, lung, heart, and intestine), the induction and repair of DSBs after irradiation with therapeutic doses (0.1-2 Gy) was investigated in repair-proficient and repair-deficient mouse strains in vivo and blood samples irradiated ex vivo. gammaH2AX-foci analysis allowed to verify the different DSB repair deficiencies; even slight impairments caused by single polymorphisms were detected similarly in both blood lymphocytes and solid tissues, indicating that DSB repair measured in lymphocytes is valid for different and complex organs. Moreover, gammaH2AX-foci analysis of blood samples irradiated ex vivo was found to reflect repair kinetics measured in vivo and, thus, give reliable information about the individual DSB repair capacity. gammaH2AX analysis of blood and tissue samples allows to detect even minor genetically defined DSB repair deficiencies, affecting normal tissue radiosensitivity. Future studies will have to evaluate the clinical potential to identify patients more susceptible to radiation toxicities before radiotherapy.
Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation?

PubMed Central

Pácal, Lukáš; Kuricová, Katarína; Kaňková, Kateřina

2014-01-01

Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given. PMID:24936250
Decreased inward rectifier potassium current IK1 in dystrophin-deficient ventricular cardiomyocytes.

PubMed

Rubi, Lena; Koenig, Xaver; Kubista, Helmut; Todt, Hannes; Hilber, Karlheinz

2017-03-04

Kir2.x channels in ventricular cardiomyocytes (most prominently Kir2.1) account for the inward rectifier potassium current I K1 , which controls the resting membrane potential and the final phase of action potential repolarization. Recently it was hypothesized that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels. To test this hypothesis, we investigated potential I K1 abnormalities in dystrophin-deficient ventricular cardiomyocytes derived from the hearts of Duchenne muscular dystrophy mouse models. We found that I K1 was substantially diminished in dystrophin-deficient cardiomyocytes when compared to wild type myocytes. This finding represents the first functional evidence for a significant role of the DAPC in the regulation of Kir2.x channels.
Treatment of Creatine Transporter (SLC6A8) Deficiency With Oral S-Adenosyl Methionine as Adjunct to L-arginine, Glycine, and Creatine Supplements.

PubMed

Jaggumantri, Sravan; Dunbar, Mary; Edgar, Vanessa; Mignone, Cristina; Newlove, Theresa; Elango, Rajavel; Collet, Jean Paul; Sargent, Michael; Stockler-Ipsiroglu, Sylvia; van Karnebeek, Clara D M

2015-10-01

Creatine transporter (SLC6A8) deficiency is an X-linked inborn error of metabolism characterized by cerebral creatine deficiency, behavioral problems, seizures, hypotonia, and intellectual developmental disability. A third of patients are amenable to treatment with high-dose oral creatine, glycine, and L-arginine supplementation. Given the limited treatment response, we initiated an open-label observational study to evaluate the effect of adjunct S-adenosyl methionine to further enhance intracerebral creatine synthesis. Significant and reproducible issues with sleep and behavior were noted in both male patients on a dose of 50/mg/kg. One of the two patients stopped S-adenosyl methionine and did not come for any follow-up. A safe and tolerable dose (17 mg/kg/day) was identified in the other patient. On magnetic resonance spectroscopy, this 8-year-old male did not show an increase in intracerebral creatine. However, significant improvement in speech/language skills, muscle mass were observed as well as in personal outcomes as defined by the family in activities related to communication and decision making. Further research is needed to assess the potential of S-adenosyl methionine as an adjunctive therapy for creatine transporter deficiency patients and to define the optimal dose. Our study also illustrates the importance of pathophysiology-based treatment, individualized outcome assessment, and patient/family participation in rare diseases research. Copyright © 2015 Elsevier Inc. All rights reserved.
Monte Carlo simulation of zinc protoporphyrin fluorescence in the retina

NASA Astrophysics Data System (ADS)

Chen, Xiaoyan; Lane, Stephen

2010-02-01

We have used Monte Carlo simulation of autofluorescence in the retina to determine that noninvasive detection of nutritional iron deficiency is possible. Nutritional iron deficiency (which leads to iron deficiency anemia) affects more than 2 billion people worldwide, and there is an urgent need for a simple, noninvasive diagnostic test. Zinc protoporphyrin (ZPP) is a fluorescent compound that accumulates in red blood cells and is used as a biomarker for nutritional iron deficiency. We developed a computational model of the eye, using parameters that were identified either by literature search, or by direct experimental measurement to test the possibility of detecting ZPP non-invasively in retina. By incorporating fluorescence into Steven Jacques' original code for multi-layered tissue, we performed Monte Carlo simulation of fluorescence in the retina and determined that if the beam is not focused on a blood vessel in a neural retina layer or if part of light is hitting the vessel, ZPP fluorescence will be 10-200 times higher than background lipofuscin fluorescence coming from the retinal pigment epithelium (RPE) layer directly below. In addition we found that if the light can be focused entirely onto a blood vessel in the neural retina layer, the fluorescence signal comes only from ZPP. The fluorescence from layers below in this second situation does not contribute to the signal. Therefore, the possibility that a device could potentially be built and detect ZPP fluorescence in retina looks very promising.
Bowman Break and Subbasal Nerve Plexus Changes in a Patient With Dry Eye Presenting With Chronic Ocular Pain and Vitamin D Deficiency.

PubMed

Shetty, Rohit; Deshpande, Kalyani; Deshmukh, Rashmi; Jayadev, Chaitra; Shroff, Rushad

2016-05-01

To report the case of a 40-year-old patient with persistent bilateral ocular pain and discomfort for 2 years in whom conventional management of dry eye had failed. Detailed ocular examination, meibography, and tear film evaluation were suggestive of bilateral meibomian gland dysfunction and evaporative dry eye. Topical medication failed to alleviate the patient's symptoms. To identify the cause of pain, imaging was performed with in vivo confocal microscopy and anterior segment spectral domain optical coherence tomography. Systemic evaluation revealed severe vitamin D deficiency with a value of 5.86 ng/mL. Case report. In vivo confocal microscopy showed abnormal subbasal nerve plexus morphology, increased dendritic cell density, and enlarged terminal nerve sprouts. A breach in the Bowman layer was detected in both eyes on spectral domain optical coherence tomography. Conventional management having failed, LipiFlow treatment (TearScience, Morrisville, NC) was performed and topical therapy with cyclosporine 0.05%, steroids, and lubricating eye drops was initiated with incomplete symptomatic relief. However, with parenteral therapy for vitamin D deficiency, there was a dramatic improvement in the patient's symptoms. Inflammation aggravated by vitamin D deficiency results in an altered epithelial profile, Bowman layer damage, recruitment of dendritic cells, and altered subbasal nerve plexus features in patients with chronic dry eye disease. These can serve as potential imaging markers for studying the underlying mechanisms in patients with dry eye disease with persisting symptoms despite aggressive conventional treatment.
Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients.

PubMed

van Geffen, Mark; Mathijssen, Natascha C J; Holme, Pål A; Laros-van Gorkom, Britta A P; van Kraaij, Marian G J; Masereeuw, Roselinde; Peyvandi, Flora; van Heerde, Waander L

2013-07-01

Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 μg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.
Oocyte spindle proteomics analysis leading to rescue of chromosome congression defects in cloned embryos

PubMed Central

Duan, Xunbao; Zhong, Zhisheng; Potireddy, Santhi; Moncada, Camilo; Merali, Salim; Latham, Keith E.

2015-01-01

Embryos produced by somatic cell nuclear transfer (SCNT) display low term developmental potential. This is associated with deficiencies in spindle composition prior to activation and at early mitotic divisions, including failure to assemble certain proteins on the spindle. The protein-deficient spindles are accompanied by chromosome congression defects prior to activation and during the first mitotic divisions of the embryo. The molecular basis for these deficiencies and how they might be avoided are unknown. Proteomic analyses of spindles isolated from normal metaphase II (MII) stage oocytes and SCNT constructs, along with a systematic immunofluorescent survey of known spindle-associated proteins were undertaken. This was the first proteomics study of mammalian oocyte spindles. The study revealed four proteins as being deficient in spindles of SCNT embryos in addition to those previously identified; these were clathrin heavy chain (CLTC), aurora B kinase, dynactin 4, and casein kinase 1 alpha. Due to substantial reduction in CLTC abundance after spindle removal, we undertook functional studies to explore the importance of CLTC in oocyte spindle function and in chromosome congression defects of cloned embryos. Using siRNA knockdown we demonstrated an essential role for CLTC in chromosome congression during oocyte maturation. We also demonstrated rescue of chromosome congression defects in SCNT embryos at the first mitosis using CLTC mRNA injection. These studies are the first to employ proteomics analyses coupled to functional interventions to rescue a specific molecular defect in cloned embryos. PMID:20883044
Regulation of yeast fatty acid desaturase in response to iron deficiency.

PubMed

Romero, Antonia María; Jordá, Tania; Rozès, Nicolas; Martínez-Pastor, María Teresa; Puig, Sergi

2018-06-01

Unsaturated fatty acids (UFA) are essential components of phospholipids that greatly contribute to the biophysical properties of cellular membranes. Biosynthesis of UFAs relies on a conserved family of iron-dependent fatty acid desaturases, whose representative in the model yeast Saccharomyces cerevisiae is Ole1. OLE1 expression is tightly regulated to adapt UFA biosynthesis and lipid bilayer properties to changes in temperature, and in UFA or oxygen availability. Despite iron deficiency being the most extended nutritional disorder worldwide, very little is known about the mechanisms and the biological relevance of fatty acid desaturases regulation in response to iron starvation. In this report, we show that endoplasmic reticulum-anchored transcription factor Mga2 activates OLE1 transcription in response to nutritional and genetic iron deficiencies. Cells lacking MGA2 display low UFA levels and do not grow under iron-limited conditions, unless UFAs are supplemented or OLE1 is overexpressed. The proteasome, E3 ubiquitin ligase Rsp5 and the Cdc48 Npl4/Ufd1 complex are required for OLE1 activation during iron depletion. Interestingly, Mga2 also activates the transcription of its own mRNA in response to iron deficiency, hypoxia, low temperature and low UFAs. MGA2 up-regulation contributes to increase OLE1 expression in these situations. These results reveal the mechanism of OLE1 regulation when iron is scarce and identify the MGA2 auto-regulation as a potential activation strategy in multiple stresses. Copyright © 2018 Elsevier B.V. All rights reserved.
Fatal coma in a young adult due to late-onset urea cycle deficiency presenting with a prolonged seizure: a case report.

PubMed

Alameri, Majid; Shakra, Mustafa; Alsaadi, Taoufik

2015-11-23

Unexplained hyperammonemic coma in adults can be a medical dilemma in the absence of triggering factors and known comorbidities. Ornithine transcarbamylase deficiency presents most commonly with hyperammonemic coma. Although a rare disorder, ornithine transcarbamylase deficiency is the most common of the urea cycle disorders, which can occur both in children, and less commonly, in adults. The urea cycle disorder is usually acquired as an X-linked trait, and very rarely, similar to our reported case, may be acquired as a "new" mutation. Mutations that lead to later-onset presentations may lead to life-threatening disease and may be unrecognized, particularly when the first clinical symptoms occur in adulthood. We report the case of a previously healthy 17-year-old white man who developed a prolonged seizure and a rapid decline in mental status leading to coma over a 3-day period. Analysis of the OTC gene showed a 119G variant, which was identified in exon 2 of the OTC gene by sequencing. A diagnosis of ornithine transcarbamylase deficiency should be considered in adult patients who present with unexplained hyperammonemic coma and for all adult patients presenting with cryptogenic new-onset seizure and laboratory finding of elevated blood ammonia levels. This reported case highlights the importance of early recognition of this potentially reversible cause of life-threatening encephalopathy, as timely recognition and appropriate treatment can be lifesaving.
Consultative Committee on Road Traffic Fatalities: trauma audit methodology.

PubMed

McDermott, F T; Cordner, S M; Tremayne, A B

2000-10-01

Since 1992 the Consultative Committee on Road Traffic Fatalities in Victoria has identified deficiencies and errors in the management of 559 road traffic fatalities in which the patients were alive on arrival of ambulance services. The Committee also assessed the preventability of deaths. Reproducibility of results using its methodology has been shown to be statistically significant. The Committee's findings and recommendations, the latter made in association with the learned Colleges and specialist Societies, led to the establishment of a Ministerial Taskforce on Trauma and Emergency Services. As a consequence, in 2000, a new trauma care system will be implemented in Victoria. This paper presents a case example demonstrating the Committee's methodology. The Committee has two 12 member multidisciplinary evaluative panels. A retrospective evaluation was made of the complete ambulance, hospital and autopsy records of eligible fatalities. The clinical and pathological findings were analysed using a comprehensive data proforma, a narrative summary and the complete records. Resulting multidisciplinary discussion problems were identified and the potential preventability of death was assessed. In the present case example the Committee identified 16 management deficiencies of which 11 were assessed as having contributed to the patient's death; the death, however, was judged to be non-preventable. The presentation of this example demonstrating the Committee's methodology may be of assistance to hospital medical staff undertaking their own major trauma audit.
PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia

PubMed Central

Floyd, Kirsten; Law, Amanda J.

2017-01-01

Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development. Here, we investigated the role of AKT3 as it relates to aspects of learning and memory and behavioral function, relevant to schizophrenia and cognitive disability, utilizing a novel murine model of Akt3 genetic deficiency. Akt3 heterozygous (Akt3-/+) or null mice (Akt3-/-) were assessed in a comprehensive test battery. Brain biochemical studies were conducted to assess the impact of Akt3 deficiency on cortical Akt/mTOR signaling. Akt3-/+ and Akt3-/- mice exhibited selective deficits of temporal order discrimination and spatial memory, tasks critically dependent on intact prefrontal-hippocampal circuitry, but showed normal prepulse inhibition, fear conditioned learning, memory for novel objects and social function. Akt3 loss-of-function, reduced brain size and dramatically impaired cortical Akt Ser473 activation in an allele-dose dependent manner. Such changes were observed in the absence of altered Akt1 or Akt2 protein expression. Concomitant reduction of the mTORC2 complex proteins, Rictor and Sin1 identifies a potential mechanism. Our findings provide novel insight into the neurodevelopmental role of Akt3, identify a non-redundant role for Akt3 in the development of prefrontal cortical-mediated cognitive function and show that Akt3 is potentially the dominant regulator of AKT/mTOR signaling in brain. PMID:28467426
Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer

PubMed Central

Ranzani, Marco; Cesana, Daniela; Bartholomae, Cynthia C.; Sanvito, Francesca; Pala, Mauro; Benedicenti, Fabrizio; Gallina, Pierangela; Sergi, Lucia Sergi; Merella, Stefania; Bulfone, Alessandro; Doglioni, Claudio; von Kalle, Christof; Kim, Yoon Jun; Schmidt, Manfred; Tonon, Giovanni; Naldini, Luigi; Montini, Eugenio

2013-01-01

Transposons and γ-retroviruses have been efficiently used as insertional mutagens in different tissues to identify molecular culprits of cancer. However, these systems are characterized by recurring integrations that accumulate in tumor cells, hampering the identification of early cancer-driving events amongst bystander and progression-related events. We developed an insertional mutagenesis platform based on lentiviral vectors (LVV) by which we could efficiently induce hepatocellular carcinoma (HCC) in 3 different mouse models. By virtue of LVV’s replication-deficient nature and broad genome-wide integration pattern, LVV-based insertional mutagenesis allowed identification of 4 new liver cancer genes from a limited number of integrations. We validated the oncogenic potential of all the identified genes in vivo, with different levels of penetrance. Our newly identified cancer genes are likely to play a role in human disease, since they are upregulated and/or amplified/deleted in human HCCs and can predict clinical outcome of patients. PMID:23314173
Biochemical and genetic analysis of Leigh syndrome patients in Korea.

PubMed

Chae, Jong-Hee; Lee, Jin Sook; Kim, Ki Joong; Hwang, Yong Seung; Hirano, Michio

2008-06-01

Sixteen Korean patients with Leigh syndrome were identified at the Seoul National University Children's Hospital in 2001-2006. Biochemical or molecular defects were identified in 14 patients (87.5%). Thirteen patients had respiratory chain enzyme defects; 9 had complex I deficiency, and 4 had combined defects of complex I+III+IV. Based on the biochemical defects, targeted genetic studies in 4 patients with complex I deficiency revealed two heteroplasmic mitochondrial DNA mutations in ND genes. One patient had the mitochondrial DNA T8993G point mutation. No mitochondrial DNA defects were identified in 11 (68.7%) of our LS patients, who probably have mutations in nuclear DNA. Although a limited study based in a single tertiary medical center, our findings suggest that isolated complex I deficiency may be the most common cause of Leigh syndrome in Korea.
Zinc Deficiency Induces Apoptosis via Mitochondrial p53- and Caspase-Dependent Pathways in Human Neuronal Precursor Cells

ERIC Educational Resources Information Center

Seth, Rohit; Corniola, Rikki S.; Gower-Winter, Shannon D.; Morgan, Thomas J., Jr.; Bishop, Brian; Levenson, Cathy W.

2015-01-01

Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent…
Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6.

PubMed

Larson, Austin A; Balasubramaniam, Shanti; Christodoulou, John; Burrage, Lindsay C; Marom, Ronit; Graham, Brett H; Diaz, George A; Glamuzina, Emma; Hauser, Natalie; Heese, Bryce; Horvath, Gabriella; Mattman, Andre; van Karnebeek, Clara; Lane Rutledge, S; Williamson, Amy; Estrella, Lissette; Van Hove, Johan K L; Weisfeld-Adams, James D

2018-01-04

Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded. Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
Proton channel HVCN1 is required for effector functions of mouse eosinophils

PubMed Central

2013-01-01

Background Proton currents are required for optimal respiratory burst in phagocytes. Recently, HVCN1 was identified as the molecule required for the voltage-gated proton channel activity associated with the respiratory burst in neutrophils. Although there are similarities between eosinophils and neutrophils regarding their mechanism for respiratory burst, the role of proton channels in eosinophil functions has not been fully understood. Results In the present study, we first identified the expression of the proton channel HVCN1 in mouse eosinophils. Furthermore, using HVCN1-deficient eosinophils, we demonstrated important cell-specific effector functions for HVCN1. Similar to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils produced significantly less reactive oxygen species (ROS) upon phorbol myristate acetate (PMA) stimulation compared with WT eosinophils. In contrast to HVCN1-deficient neutrophils, HVCN1-deficient eosinophils did not show impaired calcium mobilization or migration ability compared with wild-type (WT) cells. Uniquely, HVCN1-deficient eosinophils underwent significantly increased cell death induced by PMA stimulation compared with WT eosinophils. The increased cell death was dependent on NADPH oxidase activation, and correlated with the failure of HVCN1-deficient cells to maintain membrane polarization and intracellular pH in the physiological range upon activation. Conclusions Eosinophils require proton channel HVCN1 for optimal ROS generation and prevention of activation-induced cell death. PMID:23705768
Use of genotype-environment interactions to elucidate the pattern of maize root plasticity to nitrogen deficiency.

PubMed

Li, Pengcheng; Zhuang, Zhongjuan; Cai, Hongguang; Cheng, Shuai; Soomro, Ayaz Ali; Liu, Zhigang; Gu, Riliang; Mi, Guohua; Yuan, Lixing; Chen, Fanjun

2016-03-01

Maize (Zea mays L.) root morphology exhibits a high degree of phenotypic plasticity to nitrogen (N) deficiency, but the underlying genetic architecture remains to be investigated. Using an advanced BC4 F3 population, we investigated the root growth plasticity under two contrasted N levels and identified the quantitative trait loci (QTLs) with QTL-environment (Q × E) interaction effects. Principal components analysis (PCA) on changes of root traits to N deficiency (ΔLN-HN) showed that root length and biomass contributed for 45.8% in the same magnitude and direction on the first PC, while root traits scattered highly on PC2 and PC3. Hierarchical cluster analysis on traits for ΔLN-HN further assigned the BC4 F3 lines into six groups, in which the special phenotypic responses to N deficiency was presented. These results revealed the complicated root plasticity of maize in response to N deficiency that can be caused by genotype-environment (G × E) interactions. Furthermore, QTL mapping using a multi-environment analysis identified 35 QTLs for root traits. Nine of these QTLs exhibited significant Q × E interaction effects. Taken together, our findings contribute to understanding the phenotypic and genotypic pattern of root plasticity to N deficiency, which will be useful for developing maize tolerance cultivars to N deficiency. © 2015 Institute of Botany, Chinese Academy of Sciences.
Plasticity of DNA methylation and gene expression under zinc deficiency in Arabidopsis roots.

PubMed

Chen, Xiaochao; Schönberger, Brigitte; Menz, Jochen; Ludewig, Uwe

2018-05-25

DNA methylation is a heritable chromatin modification that maintains chromosome stability, regulates transposon silencing and appears to be involved in gene expression in response to environmental conditions. Environmental stress alters DNA methylation patterns that are correlated with gene expression differences. Here, genome-wide differential DNA-methylation was identified upon prolonged Zn deficiency, leading to hypo- and hyper-methylated chromosomal regions. Preferential CpG methylation changes occurred in gene promoters and gene bodies, but did not overlap with transcriptional start sites. Methylation changes were also prominent in transposable elements. By contrast, non-CG methylation differences were exclusively found in promoters of protein coding genes and in transposable elements. Strongly Zn deficiency-induced genes and their promoters were mostly non-methylated, irrespective of Zn supply. Differential DNA methylation in the CpG and CHG, but not in the CHH context, was found close to a few up-regulated Zn-deficiency genes. However, the transcriptional Zn-deficiency response in roots appeared little correlated with associated DNA methylation changes in promoters or gene bodies. Furthermore, under Zn deficiency, developmental defects were identified in an Arabidopsis mutant lacking non-CpG methylation. The root methylome thus responds specifically to a micro-nutrient deficiency and is important for efficient Zn utilization at low availability, but the relationship of differential methylation and differentially expressed genes is surprisingly poor.
Glucose-6-phosphate dehydrogenase deficiency in northern Mexico and description of a novel mutation.

PubMed

García-Magallanes, N; Luque-Ortega, F; Aguilar-Medina, E M; Ramos-Payán, R; Galaviz-Hernández, C; Romero-Quintana, J G; Del Pozo-Yauner, L; Rangel-Villalobos, H; Arámbula-Meraz, E

2014-08-01

Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common enzyme pathology in humans; it is X-linked inherited and causes neonatal hyperbilirubinaemia, chronic nonspherocytic haemolytic anaemia and drug-induced acute haemolytic anaemia. G6PD deficiency has scarcely been studied in the northern region of Mexico, which is important because of the genetic heterogeneity described in Mexican population. Therefore, samples from the northern Mexico were biochemically screened for G6PD deficiency, and PCR-RFLPs, and DNA sequencing used to identify mutations in positive samples. The frequency of G6PD deficiency in the population was 0.95% (n = 1993); the mutations in 86% of these samples were G6PD A(-202A/376G), G6PDA(-376G/968C) and G6PD Santamaria(376G/542T). Contrary to previous reports, we demonstrated that G6PD deficiency distribution is relatively homogenous throughout the country (P = 0.48336), and the unique exception with high frequency of G6PD deficiency does not involve a coastal population (Chihuahua: 2.4%). Analysis of eight polymorphic sites showed only 10 haplotypes. In one individual we identified a new G6PD mutation named Mexico DF(193A>G) (rs199474830), which probably results in a damaging functional effect, according to PolyPhen analysis. Proteomic impact of the mutation is also described.

The Role of Estrogens in Pancreatic Islet Physiopathology.

PubMed

Mauvais-Jarvis, Franck; Le May, Cedric; Tiano, Joseph P; Liu, Suhuan; Kilic-Berkmen, Gamze; Kim, Jun Ho

2017-01-01

In rodent models of insulin-deficient diabetes, 17β-estradiol (E2) protects pancreatic insulin-producing β-cells against oxidative stress, amyloid polypeptide toxicity, gluco-lipotoxicity, and apoptosis. Three estrogen receptors (ERs)-ERα, ERβ, and the G protein-coupled ER (GPER)-have been identified in rodent and human β-cells. This chapter describes recent advances in our understanding of the role of ERs in islet β-cell function, nutrient homeostasis, survival from pro-apoptotic stimuli, and proliferation. We discuss why and how ERs represent potential therapeutic targets for the maintenance of functional β-cell mass.
Analyses of shuttle orbiter approach and landing conditions

NASA Technical Reports Server (NTRS)

Teper, G. L.; Dimarco, R. J.; Ashkenas, I. L.; Hoh, R. H.

1981-01-01

A study of one shuttle orbiter approach and landing conditions are summarized. Causes of observed PIO like flight deficiencies are identified and potential cures are examined. Closed loop pilot/vehicle analyses are described and path/attitude stability boundaries defined. The latter novel technique proved of great value in delineating and illustrating the basic causes of this multiloop pilot control problem. The analytical results are shown to be consistent with flight test and fixed base simulation. Conclusions are drawn relating to possible improvements of the shuttle orbiter/digital flight control system.
Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells.

PubMed

Kemp, Kevin; Dey, Rimi; Cook, Amelia; Scolding, Neil; Wilkins, Alastair

2017-08-01

Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia.
Unknown Pseudocholinesterase Deficiency in a Patient Undergoing TIVA with Planned Motor Evoked Potential Monitoring: A Case Report.

PubMed

Binkley, Candace

2016-06-01

Pseudocholinesterase abnormalities are a genetic cause of aberrant metabolism of the depolarizing muscle relaxant succinylcholine. This article examines a case where succinylcholine was chosen to facilitate intubation due to its ultra short duration and the request of the surgeon to monitor motor evoked potentials. Following succinylcholine administration the neurophysiologist was unable to obtain motor evoked potentials. This case study highlights the intraoperative and postoperative management of an elderly patient with an unknown pseudocholinesterase deficiency.
Recovering from iron deficiency chlorosis in near-isogenic soybeans: a microarray study.

PubMed

O'Rourke, Jamie A; Graham, Michelle A; Vodkin, Lila; Gonzalez, Delkin Orlando; Cianzio, Silvia R; Shoemaker, Randy C

2007-05-01

Iron deficiency chlorosis (IDC) in soybeans has proven to be a perennial problem in the calcareous soils of the U.S. upper Midwest. A historically difficult trait to study in fields, the use of hydroponics in a controlled greenhouse environment has provided a mechanism to study genetic variation while limiting environmental complications. IDC susceptible plants growing in calcareous soils and in iron-controlled hydroponic experiments often exhibit a characteristic chlorotic phenotype early in the growing season but are able to re-green later in the season. To examine the changes in gene expression of these plants, near-isogenic lines, iron efficient PI548553 (Clark) and iron inefficient PI547430 (IsoClark), developed for their response to iron deficiency stress [USDA, ARS, National Genetic Resources Program, Germplasm Resources Information Network - GRIN. (Online Database) National Germplasm Resources Laboratory, Beltsville, MD, 2004. Available: http://www.ars.grin.gov/cgi-bin/npgs/html/acc_search.pl?accid=PI+547430. [22] were grown in iron-deficient hydroponic conditions for one week, then transferred to iron sufficient conditions for another week. This induced a phenotypic response mimicking the growth of the plants in the field; initial chlorosis followed by re-greening. RNA was isolated from root tissue and transcript profiles were examined between the two near-isogenic lines using publicly available cDNA microarrays. By alleviating the iron deficiency stress our expectation was that plants would return to baseline expression levels. However, the microarray comparison identified four cDNAs that were under-expressed by a two-fold or greater difference in the iron inefficient plant compared to the iron efficient plant. This differential expression was re-examined and confirmed by real time PCR experimentation. Control experiments showed that these genes are not differentially expressed in plants grown continually under iron rich hydroponic conditions. The expression differences suggest potential residual effects of iron deficiency on plant health.
Genomic Analysis of Storage Protein Deficiency in Genetically Related Lines of Common Bean (Phaseolus vulgaris)

PubMed Central

Pandurangan, Sudhakar; Diapari, Marwan; Yin, Fuqiang; Munholland, Seth; Perry, Gregory E.; Chapman, B. Patrick; Huang, Shangzhi; Sparvoli, Francesca; Bollini, Roberto; Crosby, William L.; Pauls, Karl P.; Marsolais, Frédéric

2016-01-01

A series of genetically related lines of common bean (Phaseolus vulgaris L.) integrate a progressive deficiency in major storage proteins, the 7S globulin phaseolin and lectins. SARC1 integrates a lectin-like protein, arcelin-1 from a wild common bean accession. SMARC1N-PN1 is deficient in major lectins, including erythroagglutinating phytohemagglutinin (PHA-E) but not α-amylase inhibitor, and incorporates also a deficiency in phaseolin. SMARC1-PN1 is intermediate and shares the phaseolin deficiency. Sanilac is the parental background. To understand the genomic basis for variations in protein profiles previously determined by proteomics, the genotypes were submitted to short-fragment genome sequencing using an Illumina HiSeq 2000/2500 platform. Reads were aligned to reference sequences and subjected to de novo assembly. The results of the analyses identified polymorphisms responsible for the lack of specific storage proteins, as well as those associated with large differences in storage protein expression. SMARC1N-PN1 lacks the lectin genes pha-E and lec4-B17, and has the pseudogene pdlec1 in place of the functional pha-L gene. While the α-phaseolin gene appears absent, an approximately 20-fold decrease in β-phaseolin accumulation is associated with a single nucleotide polymorphism converting a G-box to an ACGT motif in the proximal promoter. Among residual lectins compensating for storage protein deficiency, mannose lectin FRIL and α-amylase inhibitor 1 genes are uniquely present in SMARC1N-PN1. An approximately 50-fold increase in α-amylase inhibitor like protein accumulation is associated with multiple polymorphisms introducing up to eight potential positive cis-regulatory elements in the proximal promoter specific to SMARC1N-PN1. An approximately 7-fold increase in accumulation of 11S globulin legumin is not associated with variation in proximal promoter sequence, suggesting that the identity of individual proteins involved in proteome rebalancing might also be determined at the translational level. PMID:27066039
Arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Xi; Zhou, Xixi; Du, Libo

2014-01-15

Inhibition of DNA repair is a recognized mechanism for arsenic enhancement of ultraviolet radiation-induced DNA damage and carcinogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger DNA repair protein, has been identified as a sensitive molecular target for arsenic. The zinc finger domains of PARP-1 protein function as a critical structure in DNA recognition and binding. Since cellular poly(ADP-ribosyl)ation capacity has been positively correlated with zinc status in cells, we hypothesize that arsenite binding-induced zinc loss from PARP-1 is equivalent to zinc deficiency in reducing PARP-1 activity, leading to inhibition of DNA repair. To test this hypothesis, we compared the effects ofmore » arsenite exposure with zinc deficiency, created by using the membrane-permeable zinc chelator TPEN, on 8-OHdG formation, PARP-1 activity and zinc binding to PARP-1 in HaCat cells. Our results show that arsenite exposure and zinc deficiency had similar effects on PARP-1 protein, whereas supplemental zinc reversed these effects. To investigate the molecular mechanism of zinc loss induced by arsenite, ICP-AES, near UV spectroscopy, fluorescence, and circular dichroism spectroscopy were utilized to examine arsenite binding and occupation of a peptide representing the first zinc finger of PARP-1. We found that arsenite binding as well as zinc loss altered the conformation of zinc finger structure which functionally leads to PARP-1 inhibition. These findings suggest that arsenite binding to PARP-1 protein created similar adverse biological effects as zinc deficiency, which establishes the molecular mechanism for zinc supplementation as a potentially effective treatment to reverse the detrimental outcomes of arsenic exposure. - Highlights: • Arsenite binding is equivalent to zinc deficiency in reducing PARP-1 function. • Zinc reverses arsenic inhibition of PARP-1 activity and enhancement of DNA damage. • Arsenite binding and zinc loss alter the conformation of zinc finger structure.« less
Increased A20-E3 ubiquitin ligase interactions in bid-deficient glia attenuate TLR3- and TLR4-induced inflammation.

PubMed

Kinsella, Sinéad; Fichtner, Michael; Watters, Orla; König, Hans-Georg; Prehn, Jochen H M

2018-05-02

Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-κB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation. We assessed the activation of mitogen-activated protein kinase (MAPK) and interferon regulatory factor 3 (IRF3) inflammatory pathways in response to TLR3 and TLR4 agonists in wild-type (wt) and bid-deficient microglia and macrophages, using Western blot and qPCR, focusing on the response of the E3 ubiquitin ligases Pellino 1 (Peli1) and TRAF3 in the absence of microglial and astrocytic Bid. Additionally, by Western blot, we investigated the Bid-dependent turnover of Peli1 and TRAF3 in wt and bid -/- microglia using the proteasome inhibitor Bortezomib. Interactions between the de-ubiquitinating Smad6-A20 and the E3 ubiquitin ligases, TRAF3 and TRAF6, were determined by FLAG pull-down in TRAF6-FLAG or Smad6-FLAG overexpressing wt and bid-deficient mixed glia. We elucidated a positive role of Bid in both TIR-domain-containing adapter-inducing interferon-β (TRIF)- and myeloid differentiation primary response 88 (MyD88)-dependent pathways downstream of TLR4, concurrently implicating TLR3-induced inflammation. We identified that Peli1 mRNA levels were significantly reduced in PolyI:C- and lipopolysaccharide (LPS)-stimulated bid-deficient microglia, suggesting disturbed IRF3 activation. Differential regulation of TRAF3 and Peli1, both essential E3 ubiquitin ligases facilitating TRIF-dependent signaling, was observed between wt and bid -/- microglia and astrocytes. bid deficiency resulted in increased A20-E3 ubiquitin ligase protein interactions in glia, specifically A20-TRAF6 and A20-TRAF3, implicating enhanced de-ubiquitination as the mechanism of action by which E3 ligase activity is perturbed. Furthermore, Smad6-facilitated recruitment of the de-ubiquitinase A20 to E3-ligases occurred in a bid-dependent manner. This study demonstrates that Bid promotes E3 ubiquitin ligase-mediated signaling downstream of TLR3 and TLR4 and provides further evidence for the potential of Bid inhibition as a therapeutic for the attenuation of the robust pro-inflammatory response culminating in TLR activation.
Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in the Eastern Province of Saudi Arabia.

PubMed

Al-Ali, Amein K; Al-Mustafa, Zaki H; Al-Madan, Mohammed; Qaw, Foad; Al-Ateeq, Suad

2002-08-01

The level of activity of the enzyme glucose-6-phosphate dehydrogenase (G6PD) was determined in 154 unrelated Saudi males and females with G6PD deficiency who were residing in the Eastern Province of Saudi Arabia. DNA was extracted from blood samples and analyzed for known G6PD mutations by polymerase chain reaction (PCR) and restriction fragment length polymorphism techniques. Two different polymorphic mutations were identified which accounted for 90% of the samples analyzed. Of 114 G6PD-deficient males, 96 had G6PD Mediterranean, nine had African deficient variant G6PD A- and in nine the mutation has not been identified. Of the 40 G6PD-deficient females, 34 were homozygous for the G6PD Mediterranean mutation and six were genetic compound, G6PD Mediterranean/G6PD A-. The data indicate that the G6PD Mediterranean mutation is the most common (84%) in the Eastern Province, followed by G6PD A- (5.8%). Seventy one subjects who suffered from favism were found to carry the Mediterranean mutation.
Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency.

PubMed

Farhan, Sali M K; Wang, Jian; Robinson, John F; Lahiry, Piya; Siu, Victoria M; Prasad, Chitra; Kronick, Jonathan B; Ramsay, David A; Rupar, C Anthony; Hegele, Robert A

2014-01-01

Iron-sulfur (Fe-S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe-S proteins, to assist in various key biochemical pathways. Mutations in Fe-S proteins often disrupt Fe-S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron-sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe-S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology.
Iron deficiency and cognitive functions.

PubMed

Jáuregui-Lobera, Ignacio

2014-01-01

Micronutrient deficiencies, especially those related to iodine and iron, are linked to different cognitive impairments, as well as to potential long-term behavioral changes. Among the cognitive impairments caused by iron deficiency, those referring to attention span, intelligence, and sensory perception functions are mainly cited, as well as those associated with emotions and behavior, often directly related to the presence of iron deficiency anemia. In addition, iron deficiency without anemia may cause cognitive disturbances. At present, the prevalence of iron deficiency and iron deficiency anemia is 2%-6% among European children. Given the importance of iron deficiency relative to proper cognitive development and the alterations that can persist through adulthood as a result of this deficiency, the objective of this study was to review the current state of knowledge about this health problem. The relevance of iron deficiency and iron deficiency anemia, the distinction between the cognitive consequences of iron deficiency and those affecting specifically cognitive development, and the debate about the utility of iron supplements are the most relevant and controversial topics. Despite there being methodological differences among studies, there is some evidence that iron supplementation improves cognitive functions. Nevertheless, this must be confirmed by means of adequate follow-up studies among different groups.
Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.

PubMed Central

Jouanguy, E; Lamhamedi-Cherradi, S; Altare, F; Fondanèche, M C; Tuerlinckx, D; Blanche, S; Emile, J F; Gaillard, J L; Schreiber, R; Levin, M; Fischer, A; Hivroz, C; Casanova, J L

1997-01-01

Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis. PMID:9389728
RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation.

PubMed

Jones, Robert A; Robinson, Tyler J; Liu, Jeff C; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E D; Pellecchia, Giovanna; Fell, Victoria L; Bae, SooIn; Muthuswamy, Lakshmi; Datti, Alessandro; Egan, Sean E; Jiang, Zhe; Leone, Gustavo; Bader, Gary D; Schimmer, Aaron; Zacksenhaus, Eldad

2016-10-03

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration-approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.
RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

PubMed Central

Jones, Robert A.; Robinson, Tyler J.; Liu, Jeff C.; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E.D.; Pellecchia, Giovanna; Fell, Victoria L.; Bae, SooIn; Muthuswamy, Lakshmi; Egan, Sean E.; Jiang, Zhe; Leone, Gustavo; Bader, Gary D.; Schimmer, Aaron

2016-01-01

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC. PMID:27571409
The water extract of Liuwei dihuang possesses multi-protective properties on neurons and muscle tissue against deficiency of survival motor neuron protein.

PubMed

Tseng, Yu-Ting; Jong, Yuh-Jyh; Liang, Wei-Fang; Chang, Fang-Rong; Lo, Yi-Ching

2017-10-15

Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease. This study aimed to investigate the potential protection of LWDH-WE on SMN deficiency-induced neurodegeneration and muscle weakness. The effects of LWDH-WE on SMN deficiency-induced neurotoxicity and muscle atrophy were examined by using SMN-deficient NSC34 motor neuron-like cells and SMA-like mice, respectively. Inducible SMN-knockdown NSC34 motor neuron-like cells were used to mimic SMN-deficient condition. Doxycycline (1 µg/ml) was used to induce SMN deficiency in stable NSC34 cell line carrying SMN-specific shRNA. SMAΔ7 mice were used as a severe type of SMA mouse model. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Apoptotic cells and neurite length were observed by inverted microscope. Protein expressions were examined by western blots. Muscle strength of animals was evaluated by hind-limb suspension test. LWDH-WE significantly increased SMN protein level, mitochondrial membrane potential and cell viability of SMN-deficient NSC34 cells. LWDH-WE attenuated SMN deficiency-induced down-regulation of B-cell lymphoma-2 (Bcl-2) and up-regulation of cytosolic cytochrome c and cleaved caspase-3. Moreover, LWDH-WE prevented SMN deficiency-induced inhibition of neurite outgrowth and activation of Ras homolog gene family, member A (RhoA)/ Rho-associated protein kinase (ROCK2)/ phospho-LIM kinase (p-LIMK)/ phospho-cofilin (p-cofilin) pathway. Furthermore, in SMA-like mice, LWDH-WE improved muscle strength and body weight accompanied with up-regulation of SMN protein in spinal cord, brain, and gastrocnemius muscle tissues. The present study demonstrated that LWDH-WE protects motor neurons against SMN deficiency-induced neurodegeneration, and it also improves the muscle strength of SMA-like mice, suggesting the potential benefits of LWDH-WE as a complementary prescription for SMN deficiency-related diseases. Copyright © 2017 Elsevier GmbH. All rights reserved.
Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

PubMed

Dicker, Alison J; Crichton, Megan L; Cassidy, Andrew J; Brady, Gill; Hapca, Adrian; Tavendale, Roger; Einarsson, Gisli G; Furrie, Elizabeth; Elborn, J Stuart; Schembri, Stuart; Marshall, Sara E; Palmer, Colin N A; Chalmers, James D

2018-06-01

In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae , a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD. Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD. Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV 1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Presence of immune deficiency increases the risk of hospitalization in patients with norovirus infection.

PubMed

Sacco, Keith A; Pongdee, Thanai; Binnicker, Matthew J; Espy, Mark; Pardi, Darrell; Khanna, Sahil; Joshi, Avni Y

2018-04-01

Norovirus is an emerging pathogen causing gastroenteritis. We sought to identify factors associated with clinical outcomes in a cohort of patients with laboratory-confirmed norovirus infection. We performed a retrospective chart review of patients with positive norovirus polymerase chain reaction in stool between October 1, 2015, and May 31, 2016. 128 unique patients were identified during the study period, 64 of whom had immune deficiency, of which only 3 patients had a primary immune deficiency (common variable immune deficiency), while 61 patients had a secondary immune deficiency. 50% of patients with immune deficiency were hospitalized as compared to only 30% of the non-immune-deficient cohort (odds ratio: 2.1 (1.1-4.18, P=0.04). One-third (32.8%) of the patients had a polymicrobial stool infection, and 21.1% had concurrent Clostridium difficile infection. Initial mean total leukocyte count was higher in the hospitalized group at 8.40×109/L versus 6.31×109/L in the nonhospitalized group (P=0.049). All 13 patients presenting with fever had symptomatic resolution (P=0.002). The presence of C. difficile infection was correlated with persistent symptoms (OR 2.30 [0.95-5.58], P=0.067). The overall mortality rate among our cohort was 3.13% (4 patients). All deceased patients had secondary immune deficiency, and none had C. difficile coinfection. Presence of an immune deficiency increases the risk of hospitalization with norovirus infection. Absence of fever is associated with lower resolution and possibly may contribute to a persistent infectious state. Presence of concomitant C. difficile infection is correlated with a lower overall mortality rate. Copyright © 2017 Elsevier Inc. All rights reserved.
Zinc Deficiency Impacts CO2 Assimilation and Disrupts Copper Homeostasis in Chlamydomonas reinhardtii*

PubMed Central

Malasarn, Davin; Kropat, Janette; Hsieh, Scott I.; Finazzi, Giovanni; Casero, David; Loo, Joseph A.; Pellegrini, Matteo; Wollman, Francis-André; Merchant, Sabeeha S.

2013-01-01

Zinc is an essential nutrient because of its role in catalysis and in protein stabilization, but excess zinc is deleterious. We distinguished four nutritional zinc states in the alga Chlamydomonas reinhardtii: toxic, replete, deficient, and limited. Growth is inhibited in zinc-limited and zinc-toxic cells relative to zinc-replete cells, whereas zinc deficiency is visually asymptomatic but distinguished by the accumulation of transcripts encoding ZIP family transporters. To identify targets of zinc deficiency and mechanisms of zinc acclimation, we used RNA-seq to probe zinc nutrition-responsive changes in gene expression. We identified genes encoding zinc-handling components, including ZIP family transporters and candidate chaperones. Additionally, we noted an impact on two other regulatory pathways, the carbon-concentrating mechanism (CCM) and the nutritional copper regulon. Targets of transcription factor Ccm1 and various CAH genes are up-regulated in zinc deficiency, probably due to reduced carbonic anhydrase activity, validated by quantitative proteomics and immunoblot analysis of Cah1, Cah3, and Cah4. Chlamydomonas is therefore not able to grow photoautotrophically in zinc-limiting conditions, but supplementation with 1% CO2 restores growth to wild-type rates, suggesting that the inability to maintain CCM is a major consequence of zinc limitation. The Crr1 regulon responds to copper limitation and is turned on in zinc deficiency, and Crr1 is required for growth in zinc-limiting conditions. Zinc-deficient cells are functionally copper-deficient, although they hyperaccumulate copper up to 50-fold over normal levels. We suggest that zinc-deficient cells sequester copper in a biounavailable form, perhaps to prevent mismetallation of critical zinc sites. PMID:23439652
Development of performance indicators for DOTD programs.

DOT National Transportation Integrated Search

1998-05-01

The principal objectives of this study were to evaluate the performance indicators in use at DOTD, to determine if any of these indicators appeared to be deficient, and, if so, to specify those deficiencies identified, to specify a uniform procedure ...
Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency.

PubMed

Grünert, Sarah Catharina; Schmitt, Robert Niklas; Schlatter, Sonja Marina; Gemperle-Britschgi, Corinne; Balcı, Mehmet Cihan; Berg, Volker; Çoker, Mahmut; Das, Anibh M; Demirkol, Mübeccel; Derks, Terry G J; Gökçay, Gülden; Uçar, Sema Kalkan; Konstantopoulou, Vassiliki; Christoph Korenke, G; Lotz-Havla, Amelie Sophia; Schlune, Andrea; Staufner, Christian; Tran, Christel; Visser, Gepke; Schwab, Karl Otfried; Fukao, Toshiyuki; Sass, Jörn Oliver

2017-09-01

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied. Copyright © 2017 Elsevier Inc. All rights reserved.

Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination.

PubMed

Betz, U A; Vosshenrich, C A; Rajewsky, K; Müller, W

1996-10-01

The analysis of gene function based on the generation of mutant mice by homologous recombination in embryonic stem cells is limited if gene disruption results in embryonic lethality. Mosaic mice, which contain a certain proportion of mutant cells in all organs, allow lethality to be circumvented and the potential of mutant cells to contribute to different cell lineages to be analyzed. To generate mosaic animals, we used the bacteriophage P1-derived Cre-loxP recombination system, which allows gene alteration by Cre-mediated deletion of loxP-flanked gene segments. We generated nestin-cre transgenic mouse lines, which expressed the Cre recombinase under the control of the rat nestin promoter and its second intron enhancer. In crosses to animals carrying a loxP-flanked target gene, partial deletion of the loxP-flanked allele occurred before day 10.5 post coitum and was detectable in all adult organs examined, including germ-line cells. Using this approach, we generated mosaic mice containing cells deficient in the gamma-chain of the interleukin-2 receptor (IL-2R gamma); in these animals, the IL-2R gamma-deficient cells were underrepresented in the thymus and spleen. Because mice deficient in DNA polymerase beta die perinatally, we studied the effects of DNA polymerase beta deficiency in mosaic animals. We found that some of the mosaic polymerase beta-deficient animals were viable, but were often reduced in size and weight. The fraction of DNA polymerase beta-deficient cells in mosaic embryos decreased during embryonic development, presumably because wild-type cells had a competitive advantage. The nestin-cre transgenic mice can be used to generate mosaic animals in which target genes are mutated by Cre-mediated recombination of loxP-flanked target genes. By using mosaic animals, embryonic lethality can be bypassed and cell lineages for whose development a given target gene is critical can be identified. In the case of DNA polymerase beta, deficient cells are already selected against during embryonic development, demonstrating the general importance of this protein in multiple cell types.
Deficiencies in FY 1998 DOD Financial Statements and Progress Toward Improved Financial Reporting

DTIC Science & Technology

1999-11-26

DEFICIENCIES IN FY 1998 DOD FINANCIAL STATEMENTS AND PROGRESS TOWARD IMPROVED FINANCIAL REPORTING Report No. D-2000-041 November 26, 1999 Office... Financial Reporting (Report No. D-2000-041) We are providing this audit report for information and use. It identifies and summarizes the major...8FI-2025.02) Deficiencies in FY 1998 DoD Financial Statements and Progress Toward Improved Financial Reporting Executive Summary Introduction
[Cytochrome c oxydase-deficient Leigh syndrome with homozygous mutation in SURF1 gene].

PubMed

Monnot, S; Chabrol, B; Cano, A; Pellissier, J F; Collignon, P; Montfort, M F; Paquis-Flucklinger, V

2005-05-01

Leigh syndrome is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Mutations in SURF1 gene have been identified in patients with cytochrome c oxidase deficiency. We report a homozygous splice site deletion [516-2_516-1delAG] in a young girl presenting with cytochrome c oxidase-deficient Leigh syndrome. Identification of molecular defect is indispensable for genetic counselling and prenatal diagnosis.
Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency.

PubMed

Montalbano, Antonino; Juergensen, Lonny; Roeth, Ralph; Weiss, Birgit; Fukami, Maki; Fricke-Otto, Susanne; Binder, Gerhard; Ogata, Tsutomu; Decker, Eva; Nuernberg, Gudrun; Hassel, David; Rappold, Gudrun A

2016-12-01

Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three-generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.
[Prevalence of vitamin D deficiency and associated factors in women and newborns in the immediate postpartum period].

PubMed

do Prado, Mara Rúbia Maciel Cardoso; Oliveira, Fabiana de Cássia Carvalho; Assis, Karine Franklin; Ribeiro, Sarah Aparecida Vieira; do Prado Junior, Pedro Paulo; Sant'Ana, Luciana Ferreira da Rocha; Priore, Silvia Eloiza; Franceschini, Sylvia do Carmo Castro

2015-01-01

To assess the prevalence of vitamin D deficiency and its associated factors in women and their newborns in the postpartum period. This cross-sectional study evaluated vitamin D deficiency/insufficiency in 226 women and their newborns in Viçosa (Minas Gerais, BR) between December 2011 and November 2012. Cord blood and venous maternal blood were collected to evaluate the following biochemical parameters: vitamin D, alkaline phosphatase, calcium, phosphorus and parathyroid hormone. Poisson regression analysis, with a confidence interval of 95% was applied to assess vitamin D deficiency and its associated factors. Multiple linear regression analysis was performed to identify factors associated with 25(OH)D deficiency in the newborns and women from the study. The criteria for variable inclusion in the multiple linear regression model was the association with the dependent variable in the simple linear regression analysis, considering p<0.20. Significance level was α<5%. From 226 women included, 200 (88.5%) were 20 to 44 years old; the median age was 28 years. Deficient/insufficient levels of vitamin D were found in 192 (85%) women and in 182 (80.5%) neonates. The maternal 25(OH)D and alkaline phosphatase levels were independently associated with vitamin D deficiency in infants. This study identified a high prevalence of vitamin D deficiency and insufficiency in women and newborns and the association between maternal nutritional status of vitamin D and their infants' vitamin D status. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.
Vitamin A deficiency, iron deficiency, and anemia among preschool children in the Republic of the Marshall Islands.

PubMed

Palafox, Neal A; Gamble, Mary V; Dancheck, Barbara; Ricks, Michelle O; Briand, Kennar; Semba, Richard D

2003-05-01

We investigated the co-occurrence of vitamin A deficiency, iron deficiency, and anemia among young children in the Republic of the Marshall Islands. Hemoglobin, serum retinol, and serum ferritin were assessed in the Republic of the Marshall Islands Vitamin A Deficiency Study, a community-based survey that involved 919 children ages 1 to 5 y. The proportion of children with vitamin A deficiency (serum retinol concentrations < 0.70 microM/L) was 59.9%. The prevalences of anemia (hemoglobin < 110 g/L), iron deficiency (serum ferritin < 12 microg/L), and iron deficiency anemia (iron deficiency and anemia) were 36.4%, 53.5%, and 23.8%, respectively. The proportion of children who had co-occurrence of vitamin A and iron deficiencies was 33.2%. The mean ages of children with and without vitamin A deficiency were 3.2 +/- 1.4 and 2.9 +/- 1.5 y, respectively (P = 0.01), and the mean ages of those with and without iron deficiency were 2.7 +/- 1.3 and 3.5 +/- 1.4 y, respectively (P < 0.0001). Children in the Republic of the Marshall Islands, ages 1 to 5 y, are at high risk of anemia, vitamin A deficiency, and iron deficiency, and one-third of these children had the co-occurrence of vitamin A and iron deficiencies. Further investigation is needed to identify risk factors and evaluate interventions to address vitamin A and iron deficiencies among children.
Diagnosing human blood clotting deficiency.

PubMed

Ong, Chong Cheen; Gopinath, Subash C B; Rebecca, Leong Wei Xian; Perumal, Veeradasan; Lakshmipriya, Thangavel; Saheed, Mohamed Shuaib Mohamed

2018-05-15

There are different clotting factors present in blood, carries the clotting cascade and excessive bleeding may cause a deficiency in the clotting Diagnosis of this deficiency in clotting drastically reduces the potential fatality. For enabling a sensor to detect the clotting factors, suitable probes such as antibody and aptamer have been used to capture these targets on the sensing surface. Two major clotting factors were widely studied for the diagnosis of clotting deficiency, which includes factor IX and thrombin. In addition, factor IX is considered as the substitute for heparin and the prothrombotic associated with the increased thrombin generation are taking into account their prevalence. The biosensors, surface plasmon resonance, evanescent-field-coupled waveguide-mode sensor, metal-enhanced PicoGreen fluorescence and electrochemical aptasensor were well-documented and improvements have been made for high-performance sensing. We overviewed detecting factor IX and thrombin using these biosensors, for the potential application in medical diagnosis. Copyright © 2018 Elsevier B.V. All rights reserved.
Diagnosing oceanic nutrient deficiency

PubMed Central

2016-01-01

The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical–chemical–biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue ‘Biological and climatic impacts of ocean trace element chemistry’. PMID:29035255
Diagnosing oceanic nutrient deficiency

NASA Astrophysics Data System (ADS)

Moore, C. Mark

2016-11-01

The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical-chemical-biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.
Assessing the Congregate Disaster Shelter: Using Shelter Facility Assessment Data for Evaluating Potential Hazards to Occupants During Disasters.

PubMed

Cruz, Miguel A; Garcia, Stephanie; Chowdhury, Muhammad A B; Malilay, Josephine; Perea, Nancy; Williams, O Dale

Disaster shelter assessments are environmental health assessments conducted during disaster situations to evaluate the living environment of shelters for hygiene, sanitation, and safety conditions. We conducted a secondary data analysis of shelter assessment records available (n = 108) on ice storms, floods, and tornado events from 1 state jurisdiction. Descriptive statistics were used to analyze results of environmental health deficiencies found in the facilities. The greater numbers of environmental health deficiencies were associated with sanitation (26%), facility physical issues (19%), and food areas (17%). Most deficiencies were reported following ice storms, tornadoes, and flood events. This report describes the first analysis of environmental health deficiencies found in disaster shelters across a spectrum of disaster events. Although the number of records analyzed for this project was small and results may not be generalizable, this new insight into the living environment in shelter facilities offers the first analysis of deficiencies of the shelter operation and living environment that have great potential to affect the safety and health of shelter occupants.
Mutagenic cost of ribonucleotides in bacterial DNA

PubMed Central

Schroeder, Jeremy W.; Randall, Justin R.; Hirst, William G.; O’Donnell, Michael E.; Simmons, Lyle A.

2017-01-01

Replicative DNA polymerases misincorporate ribonucleoside triphosphates (rNTPs) into DNA approximately once every 2,000 base pairs synthesized. Ribonucleotide excision repair (RER) removes ribonucleoside monophosphates (rNMPs) from genomic DNA, replacing the error with the appropriate deoxyribonucleoside triphosphate (dNTP). Ribonucleotides represent a major threat to genome integrity with the potential to cause strand breaks. Furthermore, it has been shown in the bacterium Bacillus subtilis that loss of RER increases spontaneous mutagenesis. Despite the high rNTP error rate and the effect on genome integrity, the mechanism underlying mutagenesis in RER-deficient bacterial cells remains unknown. We performed mutation accumulation lines and genome-wide mutational profiling of B. subtilis lacking RNase HII, the enzyme that incises at single rNMP residues initiating RER. We show that loss of RER in B. subtilis causes strand- and sequence-context–dependent GC → AT transitions. Using purified proteins, we show that the replicative polymerase DnaE is mutagenic within the sequence context identified in RER-deficient cells. We also found that DnaE does not perform strand displacement synthesis. Given the use of nucleotide excision repair (NER) as a backup pathway for RER in RNase HII-deficient cells and the known mutagenic profile of DnaE, we propose that misincorporated ribonucleotides are removed by NER followed by error-prone resynthesis with DnaE. PMID:29078353
Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 - 2015).

PubMed

Lior, Yotam; Geyra, Assaf; Lewis, Eli C

2016-05-01

Identified as a circulating serine-protease inhibitor, the genetic deficiency of which predisposes to the development of lung emphysema, alpha1-antitrypsin (AAT) has recently been found to possess various anti-inflammatory and immunomodulatory activities outside the biochemical inhibition of serine-proteases. AAT is presently extracted from human plasma to supply life-long infusions to patients with genetic AAT deficiency. However, its newly appreciated functions point to extended therapeutic uses; these, alongside modified production attempts, represent a novel and dynamic niche of drug repurposing, set apart from addressing lung emphysema in AAT-deficient individuals. The review provides a comprehensive summary of patent-protected inventions in the field of novel clinical indications for AAT and innovations in AAT production. A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs.
Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum.

PubMed

Granado, Noelia; Lastres-Becker, Isabel; Ares-Santos, Sara; Oliva, Idaira; Martin, Eduardo; Cuadrado, Antonio; Moratalla, Rosario

2011-12-01

Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum. Consistent with these effects, Nrf2 deficiency potentiated glial activation, indicated by increased striatal expression of markers for microglia (Mac-1 and Iba-1) and astroglia (GFAP) one day after METH administration. At the same time, Nrf2 inactivation dramatically potentiated the increase in TNFα mRNA and IL-15 protein expression in GFAP+ cells in the striatum. In sharp contrast to the potentiation of striatal damage, Nrf2 deficiency did not affect METH-induced dopaminergic neuron death or expression of glial markers or proinflammatory molecules in the substantia nigra. This study uncovers a new role for Nrf2 in protection against METH-induced inflammatory and oxidative stress and striatal degeneration. Copyright © 2011 Wiley‐Liss, Inc.
The association of pagophagia with Helicobacter pylori infection in patients with iron-deficiency anemia.

PubMed

Asma, Suheyl; Boga, Can; Ozdogu, Hakan; Serin, Ender

2009-07-01

This study aimed to determine the relationship between pagophagia (compulsive ice eating) and H. pylori infection in patients with iron-deficiency anemia. We identified H. pylori infection using the (13)C-urea breath test in 45 patients with iron-deficiency anemia (group 1) and 55 patients with iron-deficiency anemia and pagophagia (group 2). Subgroups for testing oral intestinal iron absorption were randomly assigned from both groups. These subgroups consisted of (a) 10 patients with iron-deficiency anemia, (b) 10 patients with iron-deficiency anemia and pagophagia, (c) 10 patients with iron-deficiency anemia, pagophagia, and H. pylori infection before the eradication of H. pylori and (d) subgroup c after eradication therapy. There was no difference in the rate of H. pylori infection in the iron-deficiency anemia groups, with or without pagophagia. Furthermore, oral intestinal iron absorption was not influenced by pagophagia and/or H. pylori infection. Pagophagia did not increase the risk of H. pylori infection in patients with iron-deficiency anemia. Pagophagia and H. pylori infection do not synergistically affect the development of intestinal iron absorption abnormalities.
Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer.

PubMed

Telli, M L; Stover, D G; Loi, S; Aparicio, S; Carey, L A; Domchek, S M; Newman, L; Sledge, G W; Winer, E P

2018-05-07

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.
Strategies for Correcting Very Long Chain Acyl-CoA Dehydrogenase Deficiency*

PubMed Central

Tenopoulou, Margarita; Chen, Jie; Bastin, Jean; Bennett, Michael J.; Ischiropoulos, Harry; Doulias, Paschalis-Thomas

2015-01-01

Very long acyl-CoA dehydrogenase (VLCAD) deficiency is a genetic pediatric disorder presenting with a spectrum of phenotypes that remains for the most part untreatable. Here, we present a novel strategy for the correction of VLCAD deficiency by increasing mutant VLCAD enzymatic activity. Treatment of VLCAD-deficient fibroblasts, which express distinct mutant VLCAD protein and exhibit deficient fatty acid β-oxidation, with S-nitroso-N-acetylcysteine induced site-specific S-nitrosylation of VLCAD mutants at cysteine residue 237. Cysteine 237 S-nitrosylation was associated with an 8–17-fold increase in VLCAD-specific activity and concomitant correction of acylcarnitine profile and β-oxidation capacity, two hallmarks of the disorder. Overall, this study provides biochemical evidence for a potential therapeutic modality to correct β-oxidation deficiencies. PMID:25737446
Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

PubMed

Paul, James M; Toosi, Behzad; Vizeacoumar, Frederick S; Bhanumathy, Kalpana Kalyanasundaram; Li, Yue; Gerger, Courtney; El Zawily, Amr; Freywald, Tanya; Anderson, Deborah H; Mousseau, Darrell; Kanthan, Rani; Zhang, Zhaolei; Vizeacoumar, Franco J; Freywald, Andrew

2016-08-02

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.
mRNA transcripts as molecular biomarkers in medicine and nutrition

PubMed Central

Sunde, Roger A.

2010-01-01

In medicine, mRNA transcripts are being developed as molecular biomarkers for the diagnosis and treatment of a number of diseases. These biomarkers offer early and more accurate prediction and diagnosis of disease and disease progression, and ability to identify individuals at risk. Use of microarrays also offers opportunity to identify orthogonal (uncorrelated) biomarkers not known to be linked with conventional biomarkers. Investigators are increasingly using blood as a surrogate tissue for biopsy and analysis; total RNA isolated from whole blood is predominantly from erythroid cells, and whole blood mRNA share more than 80% of the transcriptome with major tissues. Thus blood mRNA biomarkers for individualized disease prediction and diagnosis are an exciting area in medicine; mRNA biomarkers in nutrition have potential application that parallel these opportunities. Assessment of selenium (Se) status and requirements is one area where tissue mRNA levels have been used successfully. Selenoprotein-H and selenoprotein-W as well as glutathione peroxidase-1 (Gpx1) mRNAs are highly down-regulated in Se deficiency in rat liver, and the minimum dietary Se requirement is 0.06–0.07 μg Se/g based on these biomarkers, similar to requirements determined using conventional biomarkers. Blood Gpx1 mRNA can also be used to determine Se requirements in rats, showing that blood mRNA has potential for assessment of nutrient status. Future research is needed to develop mRNA biomarker panels for all nutrients that will discriminate between deficient, marginal, adequate, and supernutritional individuals and populations, and differentiate between individuals that will benefit versus be adversely affected by nutrient supplementation. PMID:20303730
Quality Issues Identified During the Evaluation of Biosimilars by the European Medicines Agency's Committee for Medicinal Products for Human Use.

PubMed

Cilia, Mark; Ruiz, Sol; Richardson, Peter; Salmonson, Tomas; Serracino-Inglott, Anthony; Wirth, Francesca; Borg, John Joseph

2018-02-01

The aim of this study was to identify trends in deficiencies raised during the EU evaluation of the quality part of dossiers for marketing authorisation applications of biosimilar medicinal products. All adopted day 120 list of questions on the quality module of 22 marketing authorisation applications for biosimilars submitted to the European Medicines Agency and concluded by the end of October 2015 was analysed. Frequencies of common deficiencies identified were calculated and summarised descriptions included. Frequencies and trends on quality deficiencies were recorded and presented for 22 biosimilar applications. Thirty-two 'major objections' for 9 products were identified from 14 marketing authorisation applications with 15 raised for drug substance and 17 for drug product. In addition, 547 'other concerns' for drug substance and 495 for drug product were also adopted. The frequencies and trends of the identified deficiencies together with their impact were discussed from a regulatory perspective and how these impact key manufacturing processes and key materials used in the production of biosimilars. This study provides an insight to the regulatory challenges prospective companies need to consider when developing biosimilars; it also helps elucidate common pitfalls in the development and production of biosimilars and in the submission of dossiers for their marketing authorisations. The results are expected to be of interest to pharmaceutical companies but also to regulators to obtain consistent information on medicinal products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.
Recent insights into the Smith-Lemli-Opitz syndrome.

PubMed

Yu, H; Patel, S B

2005-11-01

Recent insights into the Smith-Lemli-Opitz syndrome. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation disorder caused by an inborn error of post-squalene cholesterol biosynthesis. Deficient cholesterol synthesis in SLOS is caused by inherited mutations of 3beta-hydroxysterol-Delta7 reductase gene (DHCR7). DHCR7 deficiency impairs both cholesterol and desmosterol production, resulting in elevated 7DHC/8DHC levels, typically decreased cholesterol levels and, importantly, developmental dysmorphology. The discovery of SLOS has led to new questions regarding the role of the cholesterol biosynthesis pathway in human development. To date, a total of 121 different mutations have been identified in over 250 patients with SLOS who represent a continuum of clinical severity. Two genetic mouse models have been generated which recapitulate some of the developmental abnormalities of SLOS and have been useful in elucidating the pathogenesis. This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS.

Antimisting kerosene JT3 engine fuel system integration study

NASA Technical Reports Server (NTRS)

Fiorentino, A.

1987-01-01

An analytical study and laboratory tests were conducted to assist NASA in determining the safety and mission suitability of the modified fuel system and flight tests for the Full-Scale Transport Controlled Impact Demonstration (CID) program. This twelve-month study reviewed and analyzed both the use of antimisting kerosene (AMK) fuel and the incorporation of a fuel degrader on the operational and performance characteristics of the engines tested. Potential deficiencies and/or failures were identified and approaches to accommodate these deficiencies were recommended to NASA Ames -Dryden Flight Research Facility. The result of flow characterization tests on degraded AMK fuel samples indicated levels of degradation satisfactory for the planned missions of the B-720 aircraft. The operability and performance with the AMK in a ground test engine and in the aircraft engines during the test flights were comparable to those with unmodified Jet A. For the final CID test, the JT-3C-7 engines performed satisfactorily while operating on AMK right up to impact.
Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy.

PubMed

Palmer, Christine D; Guinan, Eva C; Levy, Ofer

2011-08-01

BPI (bactericidal/permeability-increasing protein) is a 55 kDa anti-infective molecule expressed in neutrophil and eosinophil granules and on some epithelial cells. BPI's high affinity for the lipid A region of endotoxin targets its opsonizing, microbicidal and endotoxin-neutralizing activities towards Gram-negative bacteria. Several immunocompromised patient populations demonstrate BPI deficiency, including newborns, those with anti-neutrophil cytoplasmic antibodies (as in cystic fibrosis and HIV infection) and those exposed to radiochemotherapy. BPI may be replenished by administering agents that induce its expression or by administration of recombinant BPI congeners, potentially shielding BPI-deficient individuals against Gram-negative bacterial infection, endotoxemia and its toxic sequelae.
Use of a Questionnaire to Assess Vitamin D Status in Young Adults

PubMed Central

Bolek-Berquist, Jilaine; Elliott, Mary E.; Gangnon, Ronald E.; Gemar, Dessa; Engelke, Jean; Lawrence, Susan J.; Hansen, Karen E.

2010-01-01

Objective We hypothesized that young adults would commonly have vitamin D deficiency and that a questionnaire could help identify subjects with the condition. Design Between January and May 2004, we administered a questionnaire to a convenience sample of young adults. We measured each participant’s serum 25(OH)D using a chemiluminescent assay and defined deficiency as a serum 25(OH)D <16 ng/ml. Setting and Subjects We recruited young adults living in Madison, Wisconsin without pre-existing conditions affecting vitamin D and/or calcium metabolism. Results One hundred eighty-four adults (mean age 24 years, 53% women, 90% Caucasian) participated in the study. Nearly three in four adults (71%) had 25(OH)D levels <30 ng/ml and 26% were vitamin D deficient. In multivariate analysis, persons reporting a suntan (OR 0.24, 95% CI 0.09–0.63, p=0.004), tanning booth use (OR 0.09, 95% CI 0.02–0.43, p=0.002) and daily ingestion of two or more servings of milk (OR 0.21, 95% CI 0.09–0.48, p<0.001) were less likely to be deficient. These three questions provided a sensitivity and specificity of 79% and 78%, respectively, for the presence of deficiency. Conclusions The questionnaire is moderately useful to identify young adults likely to be vitamin D deficient. Additional revisions of the questionnaire may improve its ability to predict vitamin D deficiency. PMID:18752694
AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

PubMed Central

Hixon, Jeff; Kosinski, Penelope A.; Cianchetta, Giovanni; Histen, Gavin; Chen, Yue; Hill, Collin; Gross, Stefan; Si, Yaguang; Johnson, Kendall; DeLaBarre, Byron; Luo, Zhiyong; Gu, Zhiwei; Yao, Gui; Tang, Huachun; Fang, Cheng; Xu, Yingxia; Lv, Xiaobing; Biller, Scott; Su, Shin-San Michael; Yang, Hua; Popovici-Muller, Janeta; Salituro, Francesco; Silverman, Lee; Dang, Lenny

2017-01-01

Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit. PMID:28760888
Identification, Expression Analysis, and Target Prediction of Flax Genotroph MicroRNAs Under Normal and Nutrient Stress Conditions

PubMed Central

Melnikova, Nataliya V.; Dmitriev, Alexey A.; Belenikin, Maxim S.; Koroban, Nadezhda V.; Speranskaya, Anna S.; Krinitsina, Anastasia A.; Krasnov, George S.; Lakunina, Valentina A.; Snezhkina, Anastasiya V.; Sadritdinova, Asiya F.; Kishlyan, Natalya V.; Rozhmina, Tatiana A.; Klimina, Kseniya M.; Amosova, Alexandra V.; Zelenin, Alexander V.; Muravenko, Olga V.; Bolsheva, Nadezhda L.; Kudryavtseva, Anna V.

2016-01-01

Cultivated flax (Linum usitatissimum L.) is an important plant valuable for industry. Some flax lines can undergo heritable phenotypic and genotypic changes (LIS-1 insertion being the most common) in response to nutrient stress and are called plastic lines. Offspring of plastic lines, which stably inherit the changes, are called genotrophs. MicroRNAs (miRNAs) are involved in a crucial regulatory mechanism of gene expression. They have previously been assumed to take part in nutrient stress response and can, therefore, participate in genotroph formation. In the present study, we performed high-throughput sequencing of small RNAs (sRNAs) extracted from flax plants grown under normal, phosphate deficient and nutrient excess conditions to identify miRNAs and evaluate their expression. Our analysis revealed expression of 96 conserved miRNAs from 21 families in flax. Moreover, 475 novel potential miRNAs were identified for the first time, and their targets were predicted. However, none of the identified miRNAs were transcribed from LIS-1. Expression of seven miRNAs (miR168, miR169, miR395, miR398, miR399, miR408, and lus-miR-N1) with up- or down-regulation under nutrient stress (on the basis of high-throughput sequencing data) was evaluated on extended sampling using qPCR. Reference gene search identified ETIF3H and ETIF3E genes as most suitable for this purpose. Down-regulation of novel potential lus-miR-N1 and up-regulation of conserved miR399 were revealed under the phosphate deficient conditions. In addition, the negative correlation of expression of lus-miR-N1 and its predicted target, ubiquitin-activating enzyme E1 gene, as well as, miR399 and its predicted target, ubiquitin-conjugating enzyme E2 gene, was observed. Thus, in our study, miRNAs expressed in flax plastic lines and genotrophs were identified and their expression and expression of their targets was evaluated using high-throughput sequencing and qPCR for the first time. These data provide new insights into nutrient stress response regulation in plastic flax cultivars. PMID:27092149
7 CFR 275.15 - Data management.

Code of Federal Regulations, 2010 CFR

2010-01-01

... management information sources available to: (1) Identify all deficiencies in program operations and systems... deficiency, but after reviewing all available management information sources sufficient information is not... 7 Agriculture 4 2010-01-01 2010-01-01 false Data management. 275.15 Section 275.15 Agriculture...
Mapping of beef, sheep and goat food systems in Nairobi - A framework for policy making and the identification of structural vulnerabilities and deficiencies.

PubMed

Alarcon, Pablo; Fèvre, Eric M; Murungi, Maurice K; Muinde, Patrick; Akoko, James; Dominguez-Salas, Paula; Kiambi, Stella; Ahmed, Sohel; Häsler, Barbara; Rushton, Jonathan

2017-03-01

Nairobi is a large rapidly-growing city whose demand for beef, mutton and goat products is expected to double by 2030. The study aimed to map the Nairobi beef, sheep and goat systems structure and flows to identify deficiencies and vulnerabilities to shocks. Cross-sectional data were collected through focus group discussions and interviews with people operating in Nairobi ruminant livestock and meat markets and in the large processing companies. Qualitative and quantitative data were obtained about the type of people, animals, products and value adding activities in the chains, and their structural, spatial and temporal interactions. Mapping analysis was done in three different dimensions: people and product profiling (interactions of people and products), geographical (routes of animals and products) and temporal mapping (seasonal fluctuations). The results obtained were used to identify structural deficiencies and vulnerability factors in the system. Results for the beef food system showed that 44-55% of the city's beef supply flows through the 'local terminal markets', but that 54-64% of total supply is controlled by one 'meat market'. Numerous informal chains were identified, with independent livestock and meat traders playing a pivotal role in the functionality of these systems, and where most activities are conducted with inefficient quality control and under scarce and inadequate infrastructure and organisation, generating wastage and potential food safety risks in low quality meat products. Geographical and temporal analysis showed the critical areas influencing the different markets, with larger markets increasing their market share in the low season. Large processing companies, partly integrated, operate with high quality infrastructures, but with up to 60% of their beef supply depending on similar routes as the informal markets. Only these companies were involved in value addition activities, reaching high-end markets, but also dominating the distribution of popular products, such as beef sausages, to middle and low-end market. For the small ruminant food system, 73% of the low season supply flows through a single large informal market, Kiamaiko, located in an urban informal settlement. No grading is done for these animals or the meat produced. Large companies were reported to export up to 90% of their products. Lack of traceability and control of animal production was a common feature in all chains. The mapping presented provides a framework for policy makers and institutions to understand and design improvement plans for the Nairobi ruminant food system. The structural deficiencies and vulnerabilities identified here indicate the areas of intervention needed.
Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes.

PubMed

Penkowa, M; Giralt, M; Thomsen, P S; Carrasco, J; Hidalgo, J

2001-04-01

The role of zinc- and copper-deficient diets on the inflammatory response to traumatic brain injury (TBI) has been evaluated in adult rats. As expected, zinc deficiency decreased food intake and body weight gain, and the latter effect was higher than that observed in pair-fed rats. In noninjured brains, zinc deficiency only affected significantly lectin (increasing) and glial fibrillary acidic protein (GFAP) and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) (decreasing) immunoreactivities (irs). In injured brains, a profound gliosis was observed in the area surrounding the lesion, along with severe damage to neurons as indicated by neuron specific enolase (NSE) ir, and the number of cells undergoing apoptosis (measured by TUNEL) was dramatically increased. Zinc deficiency significantly altered brain response to TBI, potentiating the microgliosis and reducing the astrogliosis, while increasing the number of apoptotic cells. Metallothioneins (MTs) are important zinc- and copper-binding proteins in the CNS, which could influence significantly the brain response to TBI because of their putative roles in metal homeostasis and antioxidant defenses. MT-I+II expression was dramatically increased by TBI, and this response was significantly blunted by zinc deficiency. The MT-III isoform was moderately increased by both TBI and zinc deficiency. TBI strongly increased oxidative stress levels, as demonstrated by malondialdehyde (MDA), protein tyrosine nitration (NITT), and nuclear factor kappaB (NF-kappaB) levels irs, all of which were potentiated by zinc deficiency. Further analysis revealed unbalanced expression of prooxidant and antioxidant proteins besides MT, since the levels of inducible nitric oxide synthase (iNOS) and Cu,Zn-SOD were increased and decreased, respectively, by zinc deficiency. All these effects were attributable to zinc deficiency, since pair-fed rats did not differ from normally fed rats. In general, copper deficiency caused a similar pattern of responses, albeit more moderate. Results obtained in mice with a null mutation for the MT-I+II isoforms strongly suggest that most of the effects observed in the rat brain after zinc and copper deficiencies are attributable to the concomitant changes in the MT expression.
Vital Signs: Deficiencies in Environmental Control Identified in Outbreaks of Legionnaires' Disease - North America, 2000-2014.

PubMed

Garrison, Laurel E; Kunz, Jasen M; Cooley, Laura A; Moore, Matthew R; Lucas, Claressa; Schrag, Stephanie; Sarisky, John; Whitney, Cynthia G

2016-06-10

The number of reported cases of Legionnaires' disease, a severe pneumonia caused by the bacterium Legionella, is increasing in the United States. During 2000-2014, the rate of reported legionellosis cases increased from 0.42 to 1.62 per 100,000 persons; 4% of reported cases were outbreak-associated. Legionella is transmitted through aerosolization of contaminated water. A new industry standard for prevention of Legionella growth and transmission in water systems in buildings was published in 2015. CDC investigated outbreaks of Legionnaires' disease to identify gaps in building water system maintenance and guide prevention efforts. Information from summaries of CDC Legionnaires' disease outbreak investigations during 2000-2014 was systematically abstracted, and water system maintenance deficiencies from land-based investigations were categorized as process failures, human errors, equipment failures, or unmanaged external changes. During 2000-2014, CDC participated in 38 field investigations of Legionnaires' disease. Among 27 land-based outbreaks, the median number of cases was 10 (range = 3-82) and median outbreak case fatality rate was 7% (range = 0%-80%). Sufficient information to evaluate maintenance deficiencies was available for 23 (85%) investigations. Of these, all had at least one deficiency; 11 (48%) had deficiencies in ≥2 categories. Fifteen cases (65%) were linked to process failures, 12 (52%) to human errors, eight (35%) to equipment failures, and eight (35%) to unmanaged external changes. Multiple common preventable maintenance deficiencies were identified in association with disease outbreaks, highlighting the importance of comprehensive water management programs for water systems in buildings. Properly implemented programs, as described in the new industry standard, could reduce Legionella growth and transmission, preventing Legionnaires' disease outbreaks and reducing disease.
Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

PubMed

Ranganath, Prajnya; Matta, Divya; Bhavani, Gandham SriLakshmi; Wangnekar, Savita; Jain, Jamal Mohammed Nurul; Verma, Ishwar C; Kabra, Madhulika; Puri, Ratna Dua; Danda, Sumita; Gupta, Neerja; Girisha, Katta M; Sankar, Vaikom H; Patil, Siddaramappa J; Ramadevi, Akella Radha; Bhat, Meenakshi; Gowrishankar, Kalpana; Mandal, Kausik; Aggarwal, Shagun; Tamhankar, Parag Mohan; Tilak, Preetha; Phadke, Shubha R; Dalal, Ashwin

2016-10-01

Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency.

PubMed

Breitfeld, Jana; Martens, Susanne; Klammt, Jürgen; Schlicke, Marina; Pfäffle, Roland; Krause, Kerstin; Weidle, Kerstin; Schleinitz, Dorit; Stumvoll, Michael; Führer, Dagmar; Kovacs, Peter; Tönjes, Anke

2013-12-01

The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.
Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency

PubMed Central

2013-01-01

Background The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. Methods We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Results Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. Conclusions A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD. PMID:24289245
Siderophore-producing bacteria from a sand dune ecosystem and the effect of sodium benzoate on siderophore production by a potential isolate.

PubMed

Gaonkar, Teja; Nayak, Pramoda Kumar; Garg, Sandeep; Bhosle, Saroj

2012-01-01

Bioremediation in natural ecosystems is dependent upon the availability of micronutrients and cofactors, of which iron is one of the essential elements. Under aerobic and alkaline conditions, iron oxidizes to Fe(+3) creating iron deficiency. To acquire this essential growth-limiting nutrient, bacteria produce low-molecular-weight, high-affinity iron chelators termed siderophores. In this study, siderophore-producing bacteria from rhizosphere and nonrhizosphere areas of coastal sand dunes were isolated using a culture-dependent approach and were assigned to 8 different genera with the predominance of Bacillus sp. Studies on the ability of these isolates to grow on sodium benzoate revealed that a pigmented bacterial culture TMR2.13 identified as Pseudomonas aeruginosa showed growth on mineral salts medium (MSM) with 2% of sodium benzoate and produced a yellowish fluorescent siderophore identified as pyoverdine. This was inhibited above 54 μM of added iron in MSM with glucose without affecting growth, while, in presence of sodium benzoate, siderophore was produced even up to the presence of 108 μM of added iron. Increase in the requirement of iron for metabolism of aromatic compounds in ecosystems where the nutrient deficiencies occur naturally would be one of the regulating factors for the bioremediation process.
Siderophore-Producing Bacteria from a Sand Dune Ecosystem and the Effect of Sodium Benzoate on Siderophore Production by a Potential Isolate

PubMed Central

Gaonkar, Teja; Nayak, Pramoda Kumar; Garg, Sandeep; Bhosle, Saroj

2012-01-01

Bioremediation in natural ecosystems is dependent upon the availability of micronutrients and cofactors, of which iron is one of the essential elements. Under aerobic and alkaline conditions, iron oxidizes to Fe+3 creating iron deficiency. To acquire this essential growth-limiting nutrient, bacteria produce low-molecular-weight, high-affinity iron chelators termed siderophores. In this study, siderophore-producing bacteria from rhizosphere and nonrhizosphere areas of coastal sand dunes were isolated using a culture-dependent approach and were assigned to 8 different genera with the predominance of Bacillus sp. Studies on the ability of these isolates to grow on sodium benzoate revealed that a pigmented bacterial culture TMR2.13 identified as Pseudomonas aeruginosa showed growth on mineral salts medium (MSM) with 2% of sodium benzoate and produced a yellowish fluorescent siderophore identified as pyoverdine. This was inhibited above 54 μM of added iron in MSM with glucose without affecting growth, while, in presence of sodium benzoate, siderophore was produced even up to the presence of 108 μM of added iron. Increase in the requirement of iron for metabolism of aromatic compounds in ecosystems where the nutrient deficiencies occur naturally would be one of the regulating factors for the bioremediation process. PMID:22629215
Dynamics of plasma proteome during leptin-replacement therapy in genetically based leptin deficiency.

PubMed

Andreev, V P; Dwivedi, R C; Paz-Filho, G; Krokhin, O V; Wong, M-L; Wilkins, J A; Licinio, J

2011-06-01

The effects of leptin-replacement therapy on the plasma proteome of three unique adults with genetically based leptin deficiency were studied longitudinally during the course of recombinant human leptin-replacement treatment. Quantitative proteomics analysis was performed in plasma samples collected during four stages: before leptin treatment was initiated, after 1.5 and 6 years of leptin-replacement treatment, and after 7 weeks of temporary interruption of leptin-replacement therapy. Of 500 proteins reliably identified and quantitated in those four stages, about 100 were differentially abundant twofold or more in one or more stages. Synchronous dynamics of abundances of about 90 proteins was observed reflecting both short- and long-term effects of leptin-replacement therapy. Pathways and processes enriched with overabundant synchronous proteins were cell adhesion, cytoskeleton remodeling, cell cycle, blood coagulation, glycolysis, and gluconeogenesis. Plausible common regulators of the above synchronous proteins were identified using transcription regulation network analysis. The generated network included two transcription factors (c-Myc and androgen receptor) that are known to activate each other through a double-positive feedback loop, which may represent a potential molecular mechanism for the long-term effects of leptin-replacement therapy. Our findings may help to elucidate the effects of leptin on insulin resistance.
ARID1B is a specific vulnerability in ARID1A-mutant cancers.

PubMed

Helming, Katherine C; Wang, Xiaofeng; Wilson, Boris G; Vazquez, Francisca; Haswell, Jeffrey R; Manchester, Haley E; Kim, Youngha; Kryukov, Gregory V; Ghandi, Mahmoud; Aguirre, Andrew J; Jagani, Zainab; Wang, Zhong; Garraway, Levi A; Hahn, William C; Roberts, Charles W M

2014-03-01

Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.
Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yi; Wei, Wei; Wang, Yuan

Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism onmore » long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway – a pathway closely associated with synaptic plasticity and learning and memory – was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and hypothyroidism. - Highlights: • Neurotoxicity of developmental hypothyroxinemia impaired LTP. • Decreased activation of PI3K signaling contributed to LTP impairments. • The recovery of TH after the developmental period did not prevent LTP impairments. • ID diet successfully induced neurotoxicity of developmental hypothyroxinemia.« less
High prevalence of asymptomatic vitamin D and iron deficiency in East African immigrant children and adolescents living in a temperate climate

PubMed Central

McGillivray, George; Skull, Susan A; Davie, Gabrielle; Kofoed, Sarah E; Frydenberg, Alexis; Rice, James; Cooke, Regina; Carapetis, Jonathan R

2007-01-01

Objectives Vitamin D deficiency (VDD) is common in immigrant children with increased skin pigmentation living in higher latitudes. We assessed the pattern of and risk factors for VDD in immigrant East African children living in Melbourne (latitude 37°49′ South). Study design A prospective survey of 232 East African children attending a clinic in Melbourne. Data were collected by questionnaire, medical assessment and laboratory tests. Results Low 25‐hydroxyvitamin D (25‐OHD) levels (<50 nmol/l) occurred in 87% of children, and VDD (25‐OHD <25 nmol/l) in 44%. Risk factors included age <5 years, female gender, increased time in Australia, decreased daylight exposure and winter/spring season. Anaemia (20%), vitamin A deficiency (20%) and iron deficiency (19%) were also identified. Conclusions Asymptomatic VDD is common in East African immigrant children residing at a temperate latitude. Risk factors for VDD limit endogenous vitamin D production. Screening of immigrant children with increased skin pigmentation for VDD, anaemia, iron and vitamin A deficiency is appropriate. VDD in adolescent females identifies an increased risk of future infants with VDD. PMID:17768148
Concurrent outbreaks of cholera and peripheral neuropathy associated with high mortality among persons internally displaced by a volcanic eruption.

PubMed

Rosewell, Alexander; Clark, Geoff; Mabong, Paul; Ropa, Berry; Posanai, Enoch; Man, Nicola W Y; Dutta, Samir R; Wickramasinghe, Wasa; Qi, Lixia; Ng, Jack C; Mola, Glen; Zwi, Anthony B; MacIntyre, C Raina

2013-01-01

In October 2004, Manam Island volcano in Papua New Guinea erupted, causing over 10 000 villagers to flee to internally displaced person (IDP) camps, including 550 from Dugulaba village. Following violence over land access in March 2010, the IDPs fled the camps, and four months later concurrent outbreaks of acute watery diarrhea and unusual neurological complaints were reported in this population. A retrospective case-control study was conducted to identify the risk factors for peripheral neuropathy. Rectal swabs were collected from cases of acute watery diarrhea. Hair and serum metals and metalloids were analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). There were 17 deaths among the 550 village inhabitants during the outbreak period at a crude mortality rate 21-fold that of a humanitarian crisis. Vibrio cholerae O1 El Tor Ogawa was confirmed among the population. Access to community-level rehydration was crucial to mortality. Peripheral neuropathy was diagnosed among cases with neurological symptoms. A balanced diet was significantly protective against neuropathy. A dose-response relationship was seen between peripheral neuropathy and a decreasing number of micronutrient- rich foods in the diet. Deficiencies in copper, iron, selenium and zinc were identified among the cases of peripheral neuropathy. Cholera likely caused the mostly preventable excess mortality. Peripheral neuropathy was not caused by cholera, but cholera may worsen existing nutritional deficiencies. The peripheral neuropathy was likely caused by complex micronutrient deficiencies linked to non-diversified diets that potentially increased the vulnerability of this population, however a new zinc-associated neuropathy could not be ruled out. Reoccurrence can be prevented by addressing the root cause of displacement and ensuring access to arable land and timely resettlement.
Concurrent Outbreaks of Cholera and Peripheral Neuropathy Associated with High Mortality among Persons Internally Displaced by a Volcanic Eruption

PubMed Central

Rosewell, Alexander; Clark, Geoff; Mabong, Paul; Ropa, Berry; Posanai, Enoch; Man, Nicola W. Y.; Dutta, Samir R.; Wickramasinghe, Wasa; Qi, Lixia; Ng, Jack C.; Mola, Glen; Zwi, Anthony B.; MacIntyre, C. Raina

2013-01-01

Background In October 2004, Manam Island volcano in Papua New Guinea erupted, causing over 10 000 villagers to flee to internally displaced person (IDP) camps, including 550 from Dugulaba village. Following violence over land access in March 2010, the IDPs fled the camps, and four months later concurrent outbreaks of acute watery diarrhea and unusual neurological complaints were reported in this population. Materials and Methods A retrospective case-control study was conducted to identify the risk factors for peripheral neuropathy. Rectal swabs were collected from cases of acute watery diarrhea. Hair and serum metals and metalloids were analyzed by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Results There were 17 deaths among the 550 village inhabitants during the outbreak period at a crude mortality rate 21-fold that of a humanitarian crisis. Vibrio cholerae O1 El Tor Ogawa was confirmed among the population. Access to community-level rehydration was crucial to mortality. Peripheral neuropathy was diagnosed among cases with neurological symptoms. A balanced diet was significantly protective against neuropathy. A dose-response relationship was seen between peripheral neuropathy and a decreasing number of micronutrient- rich foods in the diet. Deficiencies in copper, iron, selenium and zinc were identified among the cases of peripheral neuropathy. Conclusions Cholera likely caused the mostly preventable excess mortality. Peripheral neuropathy was not caused by cholera, but cholera may worsen existing nutritional deficiencies. The peripheral neuropathy was likely caused by complex micronutrient deficiencies linked to non-diversified diets that potentially increased the vulnerability of this population, however a new zinc-associated neuropathy could not be ruled out. Reoccurrence can be prevented by addressing the root cause of displacement and ensuring access to arable land and timely resettlement. PMID:24023752

Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart.

PubMed

Lancaster, T S; Jefferson, S J; Hunter, J Craig; Lopez, Veronica; Van Eyk, J E; Lakatta, E G; Korzick, D H

2012-10-17

The incidence of myocardial infarction rises sharply at menopause, implicating a potential role for estrogen (E(2)) loss in age-related increases in ischemic injury. We aimed to identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E(2) deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary-intact or ovariectomized (OVX) rats were labeled with 8plex isobaric tags for relative and absolute quantification (iTRAQ; n = 5-6/group). Groups studied were adult, adult OVX, aged, and aged OVX. In vivo coronary artery ligation and in vitro mitochondrial respiration studies were also performed in a subset of rats. We identified 965 proteins across groups and significant directional changes in 67 proteins of aged and/or aged OVX; 32 proteins were unique to aged OVX. Notably, only six proteins were similarly altered in adult OVX (voltage-dependent ion channel 1, adenine nucleotide translocator 1, cytochrome c oxidase subunits VIIc and VIc, catalase, and myosin binding protein C). Proteins affected by aging were primarily related to cellular metabolism, oxidative stress, and cell death. The largest change occurred in monoamine oxidase-A (MAO-A), a source of oxidative stress. While acute MAO-A inhibition induced mild uncoupling in aged mitochondria, reductions in infarct size were not observed. Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E(2) deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic intervention in the aged female population.
Nitrate-induced genes in tomato roots. Array analysis reveals novel genes that may play a role in nitrogen nutrition.

PubMed

Wang, Y H; Garvin, D F; Kochian, L V

2001-09-01

A subtractive tomato (Lycopersicon esculentum) root cDNA library enriched in genes up-regulated by changes in plant mineral status was screened with labeled mRNA from roots of both nitrate-induced and mineral nutrient-deficient (-nitrogen [N], -phosphorus, -potassium [K], -sulfur, -magnesium, -calcium, -iron, -zinc, and -copper) tomato plants. A subset of cDNAs was selected from this library based on mineral nutrient-related changes in expression. Additional cDNAs were selected from a second mineral-deficient tomato root library based on sequence homology to known genes. These selection processes yielded a set of 1,280 mineral nutrition-related cDNAs that were arrayed on nylon membranes for further analysis. These high-density arrays were hybridized with mRNA from tomato plants exposed to nitrate at different time points after N was withheld for 48 h, for plants that were grown on nitrate/ammonium for 5 weeks prior to the withholding of N. One hundred-fifteen genes were found to be up-regulated by nitrate resupply. Among these genes were several previously identified as nitrate responsive, including nitrate transporters, nitrate and nitrite reductase, and metabolic enzymes such as transaldolase, transketolase, malate dehydrogenase, asparagine synthetase, and histidine decarboxylase. We also identified 14 novel nitrate-inducible genes, including: (a) water channels, (b) root phosphate and K(+) transporters, (c) genes potentially involved in transcriptional regulation, (d) stress response genes, and (e) ribosomal protein genes. In addition, both families of nitrate transporters were also found to be inducible by phosphate, K, and iron deficiencies. The identification of these novel nitrate-inducible genes is providing avenues of research that will yield new insights into the molecular basis of plant N nutrition, as well as possible networking between the regulation of N, phosphorus, and K nutrition.
A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome.

PubMed

Lim, Sze Chern; Smith, Katherine R; Stroud, David A; Compton, Alison G; Tucker, Elena J; Dasvarma, Ayan; Gandolfo, Luke C; Marum, Justine E; McKenzie, Matthew; Peters, Heidi L; Mowat, David; Procopis, Peter G; Wilcken, Bridget; Christodoulou, John; Brown, Garry K; Ryan, Michael T; Bahlo, Melanie; Thorburn, David R

2014-02-06

Leigh syndrome (LS) is a severe neurodegenerative disorder with characteristic bilateral lesions, typically in the brainstem and basal ganglia. It usually presents in infancy and is genetically heterogeneous, but most individuals with mitochondrial complex IV (or cytochrome c oxidase) deficiency have mutations in the biogenesis factor SURF1. We studied eight complex IV-deficient LS individuals from six families of Lebanese origin. They differed from individuals with SURF1 mutations in having seizures as a prominent feature. Complementation analysis suggested they had mutation(s) in the same gene but targeted massively parallel sequencing (MPS) of 1,034 genes encoding known mitochondrial proteins failed to identify a likely candidate. Linkage and haplotype analyses mapped the location of the gene to chromosome 19 and targeted MPS of the linkage region identified a homozygous c.3G>C (p.Met1?) mutation in C19orf79. Abolishing the initiation codon could potentially still allow initiation at a downstream methionine residue but we showed that this would not result in a functional protein. We confirmed that mutation of this gene was causative by lentiviral-mediated phenotypic correction. C19orf79 was recently renamed PET100 and predicted to encode a complex IV biogenesis factor. We showed that it is located in the mitochondrial inner membrane and forms a ∼300 kDa subcomplex with complex IV subunits. Previous proteomic analyses of mitochondria had overlooked PET100 because its small size was below the cutoff for annotating bona fide proteins. The mutation was estimated to have arisen at least 520 years ago, explaining how the families could have different religions and different geographic origins within Lebanon. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.

PubMed

Tredano, Mohammed; Griese, Matthias; de Blic, Jacques; Lorant, Tifenn; Houdayer, Claude; Schumacher, Silja; Cartault, François; Capron, Frédérique; Boccon-Gibod, Liliane; Lacaze-Masmonteil, Thierry; Renolleau, Sylvain; Delaisi, Bertrand; Elion, Jacques; Couderc, Rémy; Bahuau, Michel

2003-06-15

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling. Copyright 2003 Wiley-Liss, Inc.
Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.

PubMed

Olsen, Rikke K J; Koňaříková, Eliška; Giancaspero, Teresa A; Mosegaard, Signe; Boczonadi, Veronika; Mataković, Lavinija; Veauville-Merllié, Alice; Terrile, Caterina; Schwarzmayr, Thomas; Haack, Tobias B; Auranen, Mari; Leone, Piero; Galluccio, Michele; Imbard, Apolline; Gutierrez-Rios, Purificacion; Palmfeldt, Johan; Graf, Elisabeth; Vianey-Saban, Christine; Oppenheim, Marcus; Schiff, Manuel; Pichard, Samia; Rigal, Odile; Pyle, Angela; Chinnery, Patrick F; Konstantopoulou, Vassiliki; Möslinger, Dorothea; Feichtinger, René G; Talim, Beril; Topaloglu, Haluk; Coskun, Turgay; Gucer, Safak; Botta, Annalisa; Pegoraro, Elena; Malena, Adriana; Vergani, Lodovica; Mazzà, Daniela; Zollino, Marcella; Ghezzi, Daniele; Acquaviva, Cecile; Tyni, Tiina; Boneh, Avihu; Meitinger, Thomas; Strom, Tim M; Gregersen, Niels; Mayr, Johannes A; Horvath, Rita; Barile, Maria; Prokisch, Holger

2016-06-02

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Vitamin D deficiency was common among nursing home residents and associated with dementia: a cross sectional study of 545 Swedish nursing home residents.

PubMed

Arnljots, Rebeka; Thorn, Jörgen; Elm, Marie; Moore, Michael; Sundvall, Pär-Daniel

2017-10-10

Residents of nursing homes may have low 25-hydroxyvitamin D (25OHD) concentrations. Associations between vitamin D and cognitive performance, dementia and susceptibility to infections are not clearly established. The aim of this study was to investigate the prevalence of vitamin D deficiency and to identify associated factors among residents of nursing homes for elderly. In this cross-sectional study blood samples for analysis of 25OHD were collected from all participating residents of Swedish nursing homes for the elderly from January to March 2012. dementia too severe to collect a blood test, terminally ill or refusing participation. Serum 25OHD concentrations. Logistic regression to evaluate factors associated with vitamin D deficiency (25OHD < 25 nmol/L). Blood samples were obtained from 545 of 901 residents of 22 nursing homes. Mean age 86 years (SD 6.9), 68% were women. Prevalence of vitamin D supplementation 17%, dementia 55%, lack of appetite ≥3 months 45% and any antibiotic treatment during the last 6 months 30%. Serum 25OHD concentrations: mean 34 nmol/L (SD 21, median 27, range 4-125), 82% (448/545) had 25OHD < 50 nmol/L and 41% (224/545) had 25OHD < 25 nmol/L. Adjusted OR (95% CI; p-value) for possible predictors of vitamin D deficiency (25OHD < 25 nmol/L): vitamin D supplementation 0.075 (0.031-0.18; p < 0.001), lack of appetite ≥3 months 0.75 (0.50-1.1; p = 0.15), hours outdoors/week 0.99 (0.96-1.0; p = 0.62), Fitzpatrick skin phototype (4-6) 0.69 (0.44-1.1; p = 0.12); dementia 2.3 (1.5-3.4; p < 0.001) and antibiotics last 6 months 1.6 (1.1-2.6; p < 0.029), adjusted for age and gender. Vitamin D deficiency was common among nursing home residents and strongly associated with dementia. Regardless of causality or not, it is important to be alert for vitamin D deficiency in nursing homes residents with dementia. As expected vitamin D supplementation was associated with less vitamin D deficiency, however lack of appetite, staying outdoors and skin phototype were not significant predictors. Antibiotic treatments during the last 6 months were associated with vitamin D deficiency, potentially supporting the hypothesis that vitamin D deficiency is associated with infections.
Glucose-6-phosphate dehydrogenase deficiency and the sickle cell gene in Makkah, Saudi Arabia.

PubMed

el-Hazmi, M A; Warsy, A S; Bahakim, H H; al-Swailem, A

1994-02-01

This study was conducted on 689 Saudi males and females living in the Makkah area in the western province of Saudi Arabia. The frequency of severe glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in the male and female populations was 0.055 and 0.042 respectively. The normal G-6-PD was G-6-PD-B+ and the G-6-PD phenotypes identified included G-6-PD-A+, G-6-PD-A-, G-6-PD-Mediterranean, and G-6-PD-Mediterranean-like at gene frequencies of 0.0288, 0.0026, 0.05497, and 0.1969 in the male population and 0.026, 0.0146, 0.0407, and 0.02606 in the female population. The main variants producing severe and mild G-6-PD deficiency were G-6-PD-Mediterranean and G-6-PD-Mediterranean-like, respectively. The sickle cell gene was identified at a frequency of 0.029 and no interaction between sickle cell and G-6-PD deficiency genes was encountered.
Molecular characterization of G6PD deficiency in Cyprus.

PubMed

Drousiotou, Anthi; Touma, Elias H; Andreou, Nicoletta; Loiselet, Jacques; Angastiniotis, Michalis; Verrelli, Brian C; Tishkoff, Sarah A

2004-01-01

In the present study, we determined the frequency of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Cyprus using two different procedures in two separate adult population groups: a semiquantitative fluorescence test on blood spotted on filter paper and a quantitative spectrophotometric test on liquid blood. The frequency of G6PD deficiency among healthy adult males was found to be 5.1% using the semiquantitative procedure and 6.4% using the quantitative procedure. Neither method was able to detect all the expected female heterozygotes (5.3% and 47.1% of the expected number, respectively). A total of 21 male hemizygotes, 1 female homozygote and 9 female heterozygotes that tested positive for G6PD deficiency were studied at the molecular level. All 32 chromosomes were genotyped and five different mutations were identified. The Mediterranean mutation in exon 6 (563C-->T) (Ser188Phe) was found to be the most common variant in the Cypriot population, accounting for 52.6% of the deficient alleles. In the remaining chromosomes, four different mutations were identified: three known mutations, Kaiping 1388G-->A (Arg463His), Chatham 1003G-->A (Ala335Thr) and Acrokorinthos 463C-->G (His155Asp), and one previously undescribed mutation in exon 3, 148C-->T (Pro50Ser), which we called G6PD Kambos. We conclude that the frequency of G6PD deficiency in Cypriot males is 6.4%, and that this deficiency is the result of several different mutations. Although all the individuals carrying the Mediterranean variant can be detected using a semiquantitative screening method, a quantitative enzyme measurement is required to detect the G6PD variants with less severe enzyme deficiencies, while the most appropriate method for heterozygote detection is DNA analysis.
Comparative shoot proteome analysis of two potato (Solanum tuberosum L.) genotypes contrasting in nitrogen deficiency responses in vitro.

PubMed

Meise, Philipp; Jozefowicz, Anna Maria; Uptmoor, Ralf; Mock, Hans-Peter; Ordon, Frank; Schum, Annegret

2017-08-23

Aiming at a better understanding of the physiological and biochemical background of nitrogen use efficiency, alterations in the shoot proteome under N-deficiency were investigated in two contrasting potato genotypes grown in vitro with 60 and 7.5mM N, respectively. A gel based proteomic approach was applied to identify candidate proteins associated with genotype specific responses to N-deficiency. 21% of the detected proteins differed in abundance between the two genotypes. Between control and N-deficiency conditions 19.5% were differentially accumulated in the sensitive and 15% in the tolerant genotype. 93% of the highly N-deficiency responsive proteins were identified by MALDI TOF/TOF mass spectrometry. The major part was associated with photosynthesis, carbohydrate metabolism, stress response and regulation. Differential accumulation of enzymes involved in the Calvin cycle and glycolysis suggest activation of alternative carbohydrate pathways. In the tolerant genotype, increased abundance under N-deficiency was also found for enzymes involved in chlorophyll synthesis and stability of enzymes, which increase photosynthetic carbon fixation efficiency. Out of a total of 106 differentially abundant proteins, only eight were detected in both genotypes. Our findings suggest that mutually responsive proteins reflect universal stress responses while adaptation to N-deficiency in metabolic pathways is more genotype specific. Nitrogen losses from arable farm land considerably contribute to environmental pollution. In potato, this is a special problem due cultivation on light soils, irrigation and the shallow root system. Therefore, breeding of cultivars with improved nitrogen use efficiency and stable yields under reduced N fertilization is an important issue. Knowledge of genotype dependent adaptation to N-deficiency at the proteome level can help to understand regulation of N efficiency and development of N-efficient cultivars. Copyright © 2017 Elsevier B.V. All rights reserved.
Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss.

PubMed

Cao, Chike; Ren, Yinshi; Barnett, Adam S; Mirando, Anthony J; Rouse, Douglas; Mun, Se Hwan; Park-Min, Kyung-Hyun; McNulty, Amy L; Guilak, Farshid; Karner, Courtney M; Hilton, Matthew J; Pitt, Geoffrey S

2017-11-16

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.
Chemical structure and morphology of dorsal root ganglion neurons from naive and inflamed mice.

PubMed

Barabas, Marie E; Mattson, Eric C; Aboualizadeh, Ebrahim; Hirschmugl, Carol J; Stucky, Cheryl L

2014-12-05

Fourier transform infrared spectromicroscopy provides label-free imaging to detect the spatial distribution of the characteristic functional groups in proteins, lipids, phosphates, and carbohydrates simultaneously in individual DRG neurons. We have identified ring-shaped distributions of lipid and/or carbohydrate enrichment in subpopulations of neurons which has never before been reported. These distributions are ring-shaped within the cytoplasm and are likely representative of the endoplasmic reticulum. The prevalence of chemical ring subtypes differs between large- and small-diameter neurons. Peripheral inflammation increased the relative lipid content specifically in small-diameter neurons, many of which are nociceptive. Because many small-diameter neurons express an ion channel involved in inflammatory pain, transient receptor potential ankyrin 1 (TRPA1), we asked whether this increase in lipid content occurs in TRPA1-deficient (knock-out) neurons. No statistically significant change in lipid content occurred in TRPA1-deficient neurons, indicating that the inflammation-mediated increase in lipid content is largely dependent on TRPA1. Because TRPA1 is known to mediate mechanical and cold sensitization that accompanies peripheral inflammation, our findings may have important implications for a potential role of lipids in inflammatory pain. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Pathogenic Mechanisms Underlying Iron Deficiency and Iron Overload: New Insights for Clinical Application

PubMed Central

van Velden, DP; van Rensburg, SJ; Erasmus, R

2009-01-01

Iron uptake, utilisation, release and storage occur at the gene level. Individuals with variant forms of genes involved in iron metabolism may have different requirements for iron and are likely to respond differently to the same amount of iron in the diet, a concept termed nutrigenetics. Iron deficiency, iron overload and the anemia of inflammation are the commonest iron-related disorders. While at least four types of hereditary iron overload have been identified to date, our knowledge of the genetic basis and consequences of inherited iron deficiency remain limited. The importance of genetic risk factors in relation to iron overload was highlighted with the identification of the HFE gene in 1996. Deleterious mutations in this gene account for 80-90% of inherited iron overload and are associated with loss of iron homeostasis, alterations in inflammatory responses, oxidative stress and in its most severe form, the disorder hereditary haemochromatosis (HH). Elucidation of the genetic basis of HH has led to rapid clinical benefit through drastic reduction in liver biopsies performed as part of the diagnostic work-up of affected patients. Today, detection of a genetic predisposition in the presence of high serum ferritin and transferrin saturation levels is usually sufficient to diagnose HH, thereby addressing the potential danger of inherited iron overload which starts with the same symptoms as iron deficiency, namely chronic fatigue. This review provides the scientific back-up for application of pathology supported genetic testing, a new test concept that is well placed for optimizing clinical benefit to patients with regard to iron status. PMID:27683335
Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis.

PubMed

Balasubramaniam, Shanti; Lewis, Barry; Greed, Lawrence; Meili, David; Flier, Annegret; Yamamoto, Raina; Bilić, Karmen; Till, Claudia; Sass, Jörn Oliver

2016-01-01

We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900-1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband's mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase ("beta-ketothiolase") and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband's half-sister, but was absent in the proband's father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated.
Identifying deficiencies in national and foreign medical team responses through expert opinion surveys: implications for education and training.

PubMed

Djalali, Ahmadreza; Ingrassia, Pier Luigi; Corte, Francesco Della; Foletti, Marco; Gallardo, Alba Ripoll; Ragazzoni, Luca; Kaptan, Kubilay; Lupescu, Olivera; Arculeo, Chris; von Arnim, Gotz; Friedl, Tom; Ashkenazi, Michael; Heselmann, Deike; Hreckovski, Boris; Khorram-Manesh, Amir; Khorrram-Manesh, Amir; Komadina, Radko; Lechner, Kostanze; Patru, Cristina; Burkle, Frederick M; Fisher, Philipp

2014-08-01

Unacceptable practices in the delivery of international medical assistance are reported after every major international disaster; this raises concerns about the clinical competence and practice of some foreign medical teams (FMTs). The aim of this study is to explore and analyze the opinions of disaster management experts about potential deficiencies in the art and science of national and FMTs during disasters and the impact these opinions might have on competency-based education and training. This qualitative study was performed in 2013. A questionnaire-based evaluation of experts' opinions and experiences in responding to disasters was conducted. The selection of the experts was done using the purposeful sampling method, and the sample size was considered by data saturation. Content analysis was used to explore the implications of the data. This study shows that there is a lack of competency-based training for disaster responders. Developing and performing standardized training courses is influenced by shortcomings in budget, expertise, and standards. There is a lack of both coordination and integration among teams and their activities during disasters. The participants of this study emphasized problems concerning access to relevant resources during disasters. The major findings of this study suggest that teams often are not competent during the response phase because of education and training deficiencies. Foreign medical teams and medically related nongovernmental organizations (NGOs) do not always provide expected capabilities and services. Failures in leadership and in coordination among teams are also a problem. All deficiencies need to be applied to competency-based curricula.
Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

PubMed Central

Galli, Stephen J.; Tsai, Mindy; Marichal, Thomas; Tchougounova, Elena; Reber, Laurent L.; Pejler, Gunnar

2016-01-01

The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such “controversial” results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified. PMID:25727288
Satisfaction with ophthalmology residency training from the perspective of recent graduates: a cross-sectional study

PubMed Central

2013-01-01

Background Few studies have evaluated satisfaction with medical residency programs from the perspective of residents or recent graduates. Knowledge of current conditions of teaching might help to identify deficiencies and to provide adequate training. So, the aim of this study was to assess the satisfaction with residency training and to identify deficiencies in this training from the perspective of recent graduates in ophthalmology residency. Methods For this purpose, we developed a questionnaire and gaved it to recent graduates in ophthalmology residency in São Paulo, Brazil, from January to December 2010. The questions contained demographic information (age, sex and time of practice in ophthalmology), a Likert scale to evaluate the level of satisfaction with medical residency concerning clinical knowledge, surgical skills and doctor-patient relationship and questions about deficiency in clinical and surgical areas. Results The areas in which recent residency graduates were very or extremely satisfied were: acquisition of clinical knowledge (89.1%), acquisition of surgical skills (93.4%) and the development of doctor-patient relationship (74.9%). Specific areas of clinical knowledge in which they perceived more deficiency were orbit (48.3%) and ophthalmic pathology (47.9%), and in surgical skills were refractive surgery (65.9%) and orbit (59.2%) Conclusions The assessment of the satisfaction with residency training in ophthalmology from the perspective of recent graduates showed high level of satisfaction and identified specific deficiencies in ophthalmic pathology, refractive surgery and orbit. PMID:23706136
Changes in the proteomic and metabolic profiles of Beta vulgaris root tips in response to iron deficiency and resupply

PubMed Central

2010-01-01

Background Plants grown under iron deficiency show different morphological, biochemical and physiological changes. These changes include, among others, the elicitation of different strategies to improve the acquisition of Fe from the rhizosphere, the adjustment of Fe homeostasis processes and a reorganization of carbohydrate metabolism. The application of modern techniques that allow the simultaneous and untargeted analysis of multiple proteins and metabolites can provide insight into multiple processes taking place in plants under Fe deficiency. The objective of this study was to characterize the changes induced in the root tip proteome and metabolome of sugar beet plants in response to Fe deficiency and resupply. Results Root tip extract proteome maps were obtained by 2-D isoelectric focusing polyacrylamide gel electrophoresis, and approximately 140 spots were detected. Iron deficiency resulted in changes in the relative amounts of 61 polypeptides, and 22 of them were identified by mass spectrometry (MS). Metabolites in root tip extracts were analyzed by gas chromatography-MS, and more than 300 metabolites were resolved. Out of 77 identified metabolites, 26 changed significantly with Fe deficiency. Iron deficiency induced increases in the relative amounts of proteins and metabolites associated to glycolysis, tri-carboxylic acid cycle and anaerobic respiration, confirming previous studies. Furthermore, a protein not present in Fe-sufficient roots, dimethyl-8-ribityllumazine (DMRL) synthase, was present in high amounts in root tips from Fe-deficient sugar beet plants and gene transcript levels were higher in Fe-deficient root tips. Also, a marked increase in the relative amounts of the raffinose family of oligosaccharides (RFOs) was observed in Fe-deficient plants, and a further increase in these compounds occurred upon short term Fe resupply. Conclusions The increases in DMRL synthase and in RFO sugars were the major changes induced by Fe deficiency and resupply in root tips of sugar beet plants. Flavin synthesis could be involved in Fe uptake, whereas RFO sugars could be involved in the alleviation of oxidative stress, C trafficking or cell signalling. Our data also confirm the increase in proteins and metabolites related to carbohydrate metabolism and TCA cycle pathways. PMID:20565974
A review of genetic, biological, pharmacological, and clinical factors that affect carbohydrate-deficient transferrin levels.

PubMed

Fleming, Michael F; Anton, Raymond F; Spies, Claudia D

2004-09-01

Carbohydrate-deficient transferrin (CDT) is an alcohol biomarker recently approved by the U.S. Food and Drug Administration. This test is increasingly being used to detect and monitor alcohol use in a variety of health care, legal, and industrial settings. The goal of this study is to review the genetic, biological, pharmacological, and clinical factors that may affect CDT levels. A review of the literature identified 95 research articles that met the authors' criteria and reported potential interactions of a variety of factors on percent and total CDT levels. The review established 12 categories of variables that may affect CDT levels. These categories include (1) alcohol use, (2) genetic factors, (3) race, (4) gender, (5) age, (6) liver disease, (7) iron levels, (8) tobacco use, (9) medication such as estrogen and anticonvulsants, (10) metabolic factors such as body mass index and total body water, (11) chronic medical conditions such as rheumatoid arthritis, and (12) surgical patients. There is evidence that %CDT levels are affected by alcohol use, end-stage liver disease, and genetic variants. In addition to these three factors, total CDT levels (CDTect) are also affected by factors that raise transferrin levels such as iron deficiency, chronic illnesses, and menopausal status. Other potential factors such as tobacco and age appear to be confounded by alcohol use. The roles of female gender, low body mass index, chronic inflammatory diseases, and medication on CDT levels require further study. False negatives are associated with female gender, episodic lower level alcohol use, and acute trauma with blood loss. This review suggests that a number of factors are associated with false-positive CDTect and %CDT levels. CDT offers great promise to assist physicians in the care of patients to detect and monitor heavy alcohol use.
The Drosophila Tis11 protein and its effects on mRNA expression in flies.

PubMed

Choi, Youn-Jeong; Lai, Wi S; Fedic, Robert; Stumpo, Deborah J; Huang, Weichun; Li, Leping; Perera, Lalith; Brewer, Brandy Y; Wilson, Gerald M; Mason, James M; Blackshear, Perry J

2014-12-19

Members of the mammalian tristetraprolin family of CCCH tandem zinc finger proteins can bind to certain AU-rich elements (AREs) in mRNAs, leading to their deadenylation and destabilization. Mammals express three or four members of this family, but Drosophila melanogaster and other insects appear to contain a single gene, Tis11. We found that recombinant Drosophila Tis11 protein could bind to ARE-containing RNA oligonucleotides with low nanomolar affinity. Remarkably, co-expression in mammalian cells with "target" RNAs demonstrated that Tis11 could promote destabilization of ARE-containing mRNAs and that this was partially dependent on a conserved C-terminal sequence resembling the mammalian NOT1 binding domain. Drosophila Tis11 promoted both deadenylation and decay of a target transcript in this heterologous cell system. We used chromosome deletion/duplication and P element insertion to produce two types of Tis11 deficiency in adult flies, both of which were viable and fertile. To address the hypothesis that Tis11 deficiency would lead to the abnormal accumulation of potential target transcripts, we analyzed gene expression in adult flies by deep mRNA sequencing. We identified 69 transcripts from 56 genes that were significantly up-regulated more than 1.5-fold in both types of Tis11-deficient flies. Ten of the up-regulated transcripts encoded probable proteases, but many other functional classes of proteins were represented. Many of the up-regulated transcripts contained potential binding sites for tristetraprolin family member proteins that were conserved in other Drosophila species. Tis11 is thus an ARE-binding, mRNA-destabilizing protein that may play a role in post-transcriptional gene expression in Drosophila and other insects. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
The Drosophila Tis11 Protein and Its Effects on mRNA Expression in Flies*

PubMed Central

Choi, Youn-Jeong; Lai, Wi S.; Fedic, Robert; Stumpo, Deborah J.; Huang, Weichun; Li, Leping; Perera, Lalith; Brewer, Brandy Y.; Wilson, Gerald M.; Mason, James M.; Blackshear, Perry J.

2014-01-01

Members of the mammalian tristetraprolin family of CCCH tandem zinc finger proteins can bind to certain AU-rich elements (AREs) in mRNAs, leading to their deadenylation and destabilization. Mammals express three or four members of this family, but Drosophila melanogaster and other insects appear to contain a single gene, Tis11. We found that recombinant Drosophila Tis11 protein could bind to ARE-containing RNA oligonucleotides with low nanomolar affinity. Remarkably, co-expression in mammalian cells with “target” RNAs demonstrated that Tis11 could promote destabilization of ARE-containing mRNAs and that this was partially dependent on a conserved C-terminal sequence resembling the mammalian NOT1 binding domain. Drosophila Tis11 promoted both deadenylation and decay of a target transcript in this heterologous cell system. We used chromosome deletion/duplication and P element insertion to produce two types of Tis11 deficiency in adult flies, both of which were viable and fertile. To address the hypothesis that Tis11 deficiency would lead to the abnormal accumulation of potential target transcripts, we analyzed gene expression in adult flies by deep mRNA sequencing. We identified 69 transcripts from 56 genes that were significantly up-regulated more than 1.5-fold in both types of Tis11-deficient flies. Ten of the up-regulated transcripts encoded probable proteases, but many other functional classes of proteins were represented. Many of the up-regulated transcripts contained potential binding sites for tristetraprolin family member proteins that were conserved in other Drosophila species. Tis11 is thus an ARE-binding, mRNA-destabilizing protein that may play a role in post-transcriptional gene expression in Drosophila and other insects. PMID:25342740

Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada.

PubMed

Horvath, Gabriella A; Davidson, A G F; Stockler-Ipsiroglu, Sylvia G; Lillquist, Yolanda P; Waters, Paula J; Olpin, S; Andresen, B S; Palaty, Jan; Nelson, Judie; Vallance, Hilary

2008-01-01

Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is an autosomal recessive disorder of fatty acid oxidation, with potential fatal outcome. MCAD deficiency is diagnosed by acylcarnitine analysis on newborn screening blood spot cards by tandem mass spectrometry. Early diagnosis of MCAD and presymptomatic treatment can potentially reduce morbidity and mortality. To evaluate incidence, clinical outcome, biochemical and molecular phenotype of MCAD cases detected in the first three years of newborn screening in British Columbia (BC). Medium chain length acylcarnitines, octanoylcarnitine (C8) and decanoylcarnitine (C10), were measured on newborn screening blood spot cards. Out of 121,000 live births, 17 newborns had C8 values above the screening cut-off of 0.38 umol/L. Ten newborns had elevated C8 on repeat cards and were investigated further. Both C8 and C8/C10 ratios remained abnormal in all confirmed MCAD cases. Positive predictive value of screening was 58% with no false negative results. Seven patients were homozygous for the common c.985A > G MCAD mutation and three others were compound heterozygous for the c.985A > G and a second mutation. Two novel mutations were identified (c.260T > C and c.382T > A). The estimated incidence of MCAD was approximately 1:12,000 live births. Upon frequent feeding and carnitine supplementation, none of the patients had metabolic crises or adverse outcomes. Frequency of MCAD in BC is comparable to reports from other newborn screening programs. Persistence of elevated C8 levels and C8/C10 ratios in confirmed MCAD cases suggest that these are sensitive markers for newborn screening. Early detection and treatment have successfully prevented adverse health outcomes in patients with MCAD.
The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

PubMed Central

Reumann, Rebecca; Vierk, Ricardo; Zhou, Lepu; Gries, Frederice; Kraus, Vanessa; Mienert, Julia; Romswinkel, Eva; Morellini, Fabio; Ferrer, Isidre; Nicolini, Chiara; Fahnestock, Margaret; Rune, Gabriele; Glatzel, Markus; Galliciotti, Giovanna

2017-01-01

The serine protease inhibitor neuroserpin regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin expression is particularly prominent at late stages of neuronal development in most regions of the central nervous system (CNS), whereas it is restricted to regions related to learning and memory in the adult brain. The physiological expression pattern of neuroserpin, its high degree of colocalization with tPA within the CNS, together with its dysregulation in neuropsychiatric disorders, suggest a role in formation and refinement of synapses. In fact, studies in cell culture and mice point to a role for neuroserpin in dendritic branching, spine morphology, and modulation of behavior. In this study, we investigated the physiological role of neuroserpin in the regulation of synaptic density, synaptic plasticity, and behavior in neuroserpin-deficient mice. In the absence of neuroserpin, mice show a significant decrease in spine-synapse density in the CA1 region of the hippocampus, while expression of the key postsynaptic scaffold protein PSD-95 is increased in this region. Neuroserpin-deficient mice show decreased synaptic potentiation, as indicated by reduced long-term potentiation (LTP), whereas presynaptic paired-pulse facilitation (PPF) is unaffected. Consistent with altered synaptic plasticity, neuroserpin-deficient mice exhibit cognitive and sociability deficits in behavioral assays. However, although synaptic dysfunction is implicated in neuropsychiatric disorders, we do not detect alterations in expression of neuroserpin in fusiform gyrus of autism patients or in dorsolateral prefrontal cortex of schizophrenia patients. Our results identify neuroserpin as a modulator of synaptic plasticity, and point to a role for neuroserpin in learning and memory. PMID:29142062
A novel KAL1 mutation is associated with combined pituitary hormone deficiency.

PubMed

Takagi, Masaki; Narumi, Satoshi; Hamada, Riku; Hasegawa, Yukihiro; Hasegawa, Tomonobu

2014-01-01

Using a next-generation sequencing strategy, we identified a novel KAL1 missense mutation (p.His568Gln) in a patient with combined pituitary hormone deficiency, right microphthalmia, right renal aplasia and severe developmental delay. Our findings will provide additional evidence that KAL1 mutations are associated with hypopituitarism, in addition to luteinizing hormone, and follicle-stimulating hormone deficiencies, and improve our understanding of the phenotypic features and developmental course associated with KAL1 mutations.
Using color and grayscale images to teach histology to color-deficient medical students.

PubMed

Rubin, Lindsay R; Lackey, Wendy L; Kennedy, Frances A; Stephenson, Robert B

2009-01-01

Examination of histologic and histopathologic microscopic sections relies upon differential colors provided by staining techniques, such as hematoxylin and eosin, to delineate normal tissue components and to identify pathologic alterations in these components. Given the prevalence of color deficiency (commonly called "color blindness") in the general population, it is likely that this reliance upon color differentiation poses a significant obstacle for several medical students beginning a course of study that includes examination of histologic slides. In the past, first-year medical students at Michigan State University who identified themselves as color deficient were encouraged to use color transparency overlays or tinted contact lenses to filter out problematic colors. Recently, however, we have offered such students a computer monitor adjusted to grayscale for in-lab work, as well as grayscale copies of color photomicrographs for examination purposes. Grayscale images emphasize the texture of tissues and the contrasts between tissues as the students learn histologic architecture. Using this approach, color-deficient students have quickly learned to compensate for their deficiency by focusing on cell and tissue structure rather than on color variation. Based upon our experience with color-deficient students, we believe that grayscale photomicrographs may also prove instructional for students with normal (trichromatic) color vision, by encouraging them to consider structural characteristics of cells and tissues that may otherwise be overshadowed by stain colors.
Patterns and determinants of functional and absolute iron deficiency in patients undergoing cardiac rehabilitation following heart surgery.

PubMed

Tramarin, Roberto; Pistuddi, Valeria; Maresca, Luigi; Pavesi, Marco; Castelvecchio, Serenella; Menicanti, Lorenzo; de Vincentiis, Carlo; Ranucci, Marco

2017-05-01

Background Anaemia and iron deficiency are frequent following major surgery. The present study aims to identify the iron deficiency patterns in cardiac surgery patients at their admission to a cardiac rehabilitation programme, and to determine which perioperative risk factor(s) may be associated with functional and absolute iron deficiency. Design This was a retrospective study on prospectively collected data. Methods The patient population included 339 patients. Functional iron deficiency was defined in the presence of transferrin saturation <20% and serum ferritin ≥100 µg/l. Absolute iron deficiency was defined in the presence of serum ferritin values <100 µg/l. Results Functional iron deficiency was found in 62.9% of patients and absolute iron deficiency in 10% of the patients. At a multivariable analysis, absolute iron deficiency was significantly ( p = 0.001) associated with mechanical prosthesis mitral valve replacement (odds ratio 5.4, 95% confidence interval 1.9-15) and tissue valve aortic valve replacement (odds ratio 4.5, 95% confidence interval 1.9-11). In mitral valve surgery, mitral repair carried a significant ( p = 0.013) lower risk of absolute iron deficiency (4.4%) than mitral valve replacement with tissue valves (8.3%) or mechanical prostheses (22.5%). Postoperative outcome did not differ between patients with functional iron deficiency and patients without iron deficiency; patients with absolute iron deficiency had a significantly ( p = 0.017) longer postoperative hospital stay (median 11 days) than patients without iron deficiency (median nine days) or with functional iron deficiency (median eight days). Conclusions Absolute iron deficiency following cardiac surgery is more frequent in heart valve surgery and is associated with a prolonged hospital stay. Routine screening for iron deficiency at admission in the cardiac rehabilitation unit is suggested.
Complement deficiency predisposes for meningitis due to nongroupable meningococci and Neisseria-related bacteria.

PubMed

Fijen, C A; Kuijper, E J; Tjia, H G; Daha, M R; Dankert, J

1994-05-01

Nongroupable meningococci or bacteria related to the genus Neisseria rarely cause meningitis. Complement deficiency has been identified as a major predisposing factor for meningococcal disease. To assess whether patients with meningitis due to such strains have a complement deficiency, we studied 12 persons. Six patients had meningitis due to nongroupable strains of meningococci, and six patients had meningitis due to Moraxella species or Acinetobacter species. Inherited complement component C7 or C8 deficiency was found in two persons who had had meningitis due to nongroupable meningococci, and one C8-deficient person had had meningitis caused by Moraxella osloensis. Hypocomplementemia resulting from CSF drain-associated shunt nephritis was found in one person with meningitis due to Moraxella nonliquefaciens and in one person with meningitis due to Acinetobacter lwoffi. This rather high frequency of inherited or acquired complement deficiencies among patients with meningitis due to nongroupable meningococci, Moraxella species, and Acinetobacter species justifies the recommendation that such patients must be studied for complement deficiency.
Prevalence of anemia and micronutrient deficiencies in early pregnancy in rural Bangladesh, the MINIMat trial.

PubMed

Lindström, Emma; Hossain, Mohammad B; Lönnerdal, Bo; Raqib, Rubhana; El Arifeen, Shams; Ekström, Eva-Charlotte

2011-01-01

To describe the prevalence of anemia and micronutrient deficiencies as well as their determinants in early pregnancy. Baseline data from a population-based randomized intervention trial. The study was conducted in Matlab, a sub-district in rural Bangladesh from 1 January to 31 December 2002. Pregnant women (n= 740) were enrolled in approximately week 14 in pregnancy. Data were collected using questionnaires, physical examinations and laboratory analyses of blood samples for concentrations of hemoglobin, ferritin, zinc, folate and vitamin B-12. Covariates associated with anemia and micronutrient deficiencies in bivariate analyses were evaluated in multivariate logistic regression models adjusting for potential confounders. Anemia was present in 28% of the women, 55% were zinc deficient, 46% were vitamin B-12 deficient and 18% were folate deficient. Anemia was not associated with iron deficiency but rather with vitamin B-12 deficiency. Infestation with Ascaris was highly prevalent (67%) and associated with both folate and vitamin B-12 deficiency. Anemia and micronutrient deficiencies all varied significantly with season. The high prevalences of zinc and vitamin B-12 deficiencies in early pregnancy are a concern, as it could lead to adverse pregnancy outcomes and increased health risks for both mother and child. The prevalence of iron deficiency was low, but as this was during early pregnancy, the women might develop iron deficiency and consequently iron deficiency anemia as the pregnancy progresses. © 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2010 Nordic Federation of Societies of Obstetrics and Gynecology.
Groups at potentially high risk from chlorine dioxide treated water.

PubMed

Moore, G S; Calabrese, E J; Ho, S C

1980-09-01

Chlorite, a by-product of chlorine dioxide disinfection of water, is a strong oxidant compound that produces markedly exaggerated effects in vitro on red cells of G6PD deficient humans when compared to normal human cells. Levels of methemoglobin are significantly greater and GSH levels significantly lower in the G6PD deficient cells than in normal cells after chlorite exposure. Persons with G6PD deficiency may be 3 to 4 times more likely to develop hemolytic anemia from chlorite exposure as persons with normal activity levels when GSH levels are used as a measure of susceptibility. The proposed use of chlorine dioxide as an alternate disinfectant for drinking water supplies should consider this potential high risk group.
Government review of the Mod-2 wind turbine (as-built)

NASA Technical Reports Server (NTRS)

Johnson, W. R.; Birchenough, A. G.; Linscott, B. S.; Reagan, J. R.; Sirocky, P. J.; Sizemore, R. L.; Sullivan, T. L.; Holeman, R. H.

1985-01-01

The findings and recommendations of the Government committee formed to conduct an as-built review of the three Mod-2 wind turbine units at Goldendale, Washington are given. The purpose of the review was to identify any critical deficiencies in machine components that could result in failure, and to recommend any necessary corrective action before resuming safe machine operation. The review concluded that one of the deficiencies identified would preclude planned attended or unattended operation, provided that certain corrective actions were implemented.
Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer

PubMed Central

Vashi, Pankaj; Edwin, Persis; Popiel, Brenten; Lammersfeld, Carolyn; Gupta, Digant

2016-01-01

Background/Aims Normal or high serum vitamin B-12 levels can sometimes be seen in a B-12 deficient state, and can therefore be misleading. High levels of Methymalonic Acid (MMA) and Homocysteine (HC) have been identified as better indicators of B-12 deficiency than the actual serum B-12 level itself. We evaluated the prevalence of vitamin B-12 deficiency using appropriate cut-off levels of vitamin B-12, MMA and HC, and determined the relationship between serum levels of vitamin B-12, MMA and HC in cancer. Methods This is a cross-sectional study using a consecutive case series of 316 cancer patients first seen at Cancer Treatment Centers of America® (CTCA) at Midwestern Regional Medical Center between April 2014 and June 2014. All patients were evaluated at baseline for vitamin B-12 (pg/mL), MMA (nmol/L) and HC (μmol/L) levels. In accordance with previously published research, the following cut-offs were used to define vitamin B-12 deficiency: <300 pg/mL for vitamin B-12, >260 nmol/L for MMA and >12 μmol/L for HC. The relationship between B-12, MMA and HC was evaluated using Spearman's rho correlation coefficient and cross-tabulation analysis. Receiver Operating Characteristic (ROC) curves were estimated using the non-parametric method to further evaluate the diagnostic accuracy of vitamin B-12 using Fedosov quotient as the "gold standard". Results Mean age at presentation was 52.5 years. 134 (42.4%) patients were males while 182 (57.6%) were females. Median vitamin B-12, MMA and HC levels were 582.5 pg/mL, 146.5 nmol/L and 8.4 μmol/L respectively. Of 316 patients, 28 (8.9%) were vitamin B-12 deficient based on vitamin B-12 (<300pg/mL), 34 (10.8%) were deficient based on MMA (>260 nmol/L) while 55 (17.4%) were deficient based on HC (>12 μmol/L). Correlation analysis revealed a significant weak negative correlation between vitamin B-12 and MMA (rho = -0.22) as well as B-12 and HC (rho = -0.35). ROC curves suggested MMA to have the best discriminatory power in predicting B-12 deficiency. Conclusion Vitamin B-12 is poorly correlated with MMA and HC in cancer. Using serum vitamin B-12 alone to evaluate B-12 status in cancer may fail to identify those with functional deficiency. A thorough clinical assessment is important to identify patients that may have risk factors and/or symptoms suggestive of deficiency. These patients should have additional testing of MMA and HC regardless of their B-12 levels. PMID:26807790
Role of micronutrients for physical growth and mental development.

PubMed

Singh, Meharban

2004-01-01

Due to control of florid and severe cases of protein-energy malnutrition, deficiencies of micronutrients in children have assumed public health importance. According to National Nutrition Monitoring Bureau of India, over 50% of apparently healthy looking children have subclinical or biochemical deficiencies of vitamin A, vitamins B2, B6, folate and vitamin C. Over two-third of children have clinical evidences of iron deficiency while deficiency of trace minerals like iodine and zinc is quite common in certain populations. Children have food preferences and they are quite fussy to take green leafy vegetables and fruits thus compromising their intake of micronutrients from dietary sources. The full genetic potential of the child for physical growth and mental development may be compromised due to subclinical deficiencies of micronutrients which are commonly referred to as "hidden hunger". Micronutrients are required for the integrity and optimal functioning of immune system. Children with subclinical deficiency of micronutrients are more vulnerable to develop frequent and more severe common day-to-day infections thus triggering a vicious cycle of undernutrition and recurrent infections. A number of micronutrients are required for optimal physical growth and neuromotor development. Isolated deficiencies of micronutrients are rare in clinical practice and usually deficiencies of multiple micronutrients co-exist. The first 3 years of life are most crucial and vulnerable to the hazards of undernutrition. All efforts should be made so that preschool children are given a balanced and nutritious home-based diet. However, it has been shown that it is not possible to meet 100% requirements of recommended dietary allowances (RDA's) of micronutrients from dietary sources alone and most preschool children need administration of nutritional supplements to optimize their genetic potential for physical growth and mental development.
High Prevalence of Vitamin D Deficiency among Iranian Population: A Systematic Review and Meta-Analysis

PubMed Central

Tabrizi, Reza; Moosazadeh, Mahmood; Akbari, Maryam; Dabbaghmanesh, Mohammad Hossein; Mohamadkhani, Minoo; Asemi, Zatollah; Heydari, Seyed Taghi; Akbari, Mojtaba; Lankarani, Kamran B

2018-01-01

Background The prevention and correction of vitamin D deficiency requires a precise depiction of the current situation and identification of risk factors in each region. The present study attempted to determine these entities using a systematic review and meta-analysis in Iran. Methods Articles published online in Persian and English between 2000 and November 1, 2016, were reviewed. This was carried out using national databases such as SID, IranMedex, Magiran, and IranDoc and international databases such as PubMed, Google Scholar, and Scopus. The heterogeneity index among the studies was determined using the Cochran (Q) and I2 test. Based on the heterogeneity results, the random-effect model was applied to estimate the prevalence of vitamin D deficiency. In addition, meta-regression analysis was used to determine heterogeneity-suspected factors, and the Egger test was applied to identify publication bias. Results The meta-analysis of 48 studies identified 18531 individuals with vitamin D deficiency. According to the random-effect model, the prevalence of vitamin D deficiency among male, female, and pregnant women was estimated to be 45.64% (95% CI: 29.63 to 61.65), 61.90% (95% CI: 48.85 to 74.96), and 60.45% (95% CI: 23.73 to 97.16), respectively. The results of the meta-regression analysis indicated that the prevalence of vitamin D deficiency was significantly different in various geographical regions (β=4.4; P=0.023). Conclusion The results obtained showed a significant prevalence of vitamin D deficiency among the Iranian population, a condition to be addressed by appropriate planning. PMID:29749981
Congenital Proprotein Convertase 1/3 Deficiency Causes Malabsorptive Diarrhea and other Endocrinopathies in a Pediatric Cohort

PubMed Central

Martín, Martín G.; Lindberg, Iris; Solorzano-Vargas, R. Sergio; Wang, Jiafang; Avitzur, Yaron; Bandsma, Robert; Sokollik, Christiane; Lawrence, Sarah; Pickett, Lindsay A.; Chen, Zijun; Egritas, Odul; Dalgic, Buket; Albornoz, Valeria; de Ridder, Lissy; Hulst, Jessie; Gok, Faysal; Aydoğan, Ayşen; Al-Hussaini, Abdulrahman; Gok, Deniz Engin; Yourshaw, Michael; Wu, S. Vincent; Cortina, Galen; Stanford, Sara; Georgia, Senta

2013-01-01

Background & Aims Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal recessive disorder caused by rare mutations in the PCSK1 gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 have also been associated with obesity in heterozygotes in several population studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. Methods We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. Results We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. Conclusion In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in processing of one or more enteric hormones that are required for nutrient absorption. PMID:23562752
Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.

PubMed

Stockler-Ipsiroglu, Sylvia; van Karnebeek, Clara D M

2014-07-01

Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency.

PubMed

Idkowiak, Jan; Randell, Tabitha; Dhir, Vivek; Patel, Pushpa; Shackleton, Cedric H L; Taylor, Norman F; Krone, Nils; Arlt, Wiebke

2012-03-01

Isolated 17,20 lyase deficiency is commonly defined by apparently normal 17α-hydroxylase activity but severely reduced 17,20 lyase activity of the bifunctional enzyme cytochrome P450 (CYP) enzyme 17A1 (CYP17A1), resulting in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. Cytochrome b5 (CYB5A) is thought to selectively enhance 17,20 lyase activity by facilitating the allosteric interaction of CYP17A1 with its electron donor P450 oxidoreductase (POR). We investigated a large consanguineous family including three siblings with 46,XY disorder of sex development (DSD) presenting with isolated 17,20 lyase deficiency. We investigated the clinical and biochemical phenotype, conducted genetic analyses, and functionally characterized the identified CYB5A mutation in cell-based CYP17A1 coexpression assays. All three siblings presented with 46,XY DSD, sex steroid deficiency, normal mineralocorticoids and glucocorticoids, and a urine steroid metabolome suggestive of isolated 17,20 lyase deficiency. CYP17A1 and POR sequences were normal, but we detected a homozygous CYB5A missense mutation (g.28,400A→T; p.H44L). Functional in vitro analysis revealed normal CYP17A1 17α-hydroxylase activity but severely impaired 17,20 lyase activity. In silico analysis suggested the disruption of CYB5A heme binding by p.H44L. We have identified the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY DSD. Detailed review of previously reported cases with apparently isolated 17,20 lyase deficiency due to mutant CYP17A1 and POR reveals impaired 17α-hydroxylase activity as assessed by steroid metabolome analysis and short cosyntropin testing. This suggests that truly isolated 17,20 lyase deficiency is observed only in individuals with inactivating CYB5A mutations.
Impairment of acquired color vision in multiple sclerosis: an early diagnostic sign linked to the greatness of disease.

PubMed

Piro, Anna; Tagarelli, Antonio; Nicoletti, Giuseppe; Scannapieco, Sara; Polidoro, Serena; Valentino, Paola; Quattrone, Aldo

2018-02-01

To assess the type and degree of both red-green and blue-yellow color vision deficiencies of Calabrian males affected by multiple sclerosis. Eighty Calabrian male patients were enrolled (age range 18-70 years; mean age 40.6 ± 12.4 years) showing a disease duration mean of 10.6 ± 8.2 years (range = 0.5-46 years) coming from the Institute of Neurology, Magna Graecia University, Catanzaro. Optic neuritis present in the medical histories of the 21 patients does not influence color vision. Excluding seven colorblind subjects and one affected by a bilateral maculopathy, the analyzed sample group was 72. Seventy controls were matched for age and sex. An ophthalmologist examined all patients and controls in order to rule out diabetic retinopathy, cataracts, senile maculopathy, or ocular fundus' anomalies. The Ishihara test identified the colorblind patients. The City University Test screened for people with abnormal color vision by grading the severity of color vision deficiency. The second part of the City University Test as well as the Farnsworth Test confirmed both the color vision deficiency type and degree. Fifty-one percentage (37/72) of the patients showing a color vision deficiency were subdivided into two subgroups: subgroup one showed red-green deficiency (57%, 21/37); subgroup two showed a coupled red-green and blue-yellow deficiency (43%, 16/37). Furthermore, we found two distinct curves showing a groove within the first 10 years of the disease. Both monocular and binocular analyses allowed us to identify the patients showing the monocular color vision deficiency, but they were well compensated by binocular vision. We think that the majority of the patients with the red-green deficiency will develop the coupled red-green and blue-yellow deficiency in the latter years of multiple sclerosis.
Enhancing nutritiousness of lamb meat and preventing selenium deficiency.

USDA-ARS?s Scientific Manuscript database

Lamb meat is a naturally flavorful and nutritious product. Our research indicates that feeding a specific wheat-milling coproduct will enhance the nutritiousness of lamb, potentially add monetary value to lamb, and prevent Se deficiency. Selenium is an essential micromineral, and Se supplementation ...
Estrogen deficiency inhibits the odonto/osteogenic differentiation of dental pulp stem cells via activation of the NF-κB pathway.

PubMed

Wang, Yanping; Yan, Ming; Yu, Yan; Wu, Jintao; Yu, Jinhua; Fan, Zhipeng

2013-06-01

Various factors can affect the functions of dental pulp stem cells (DPSCs). However, little knowledge is available about the effects of estrogen deficiency on the differentiation of DPSCs. In this study, an estrogen-deficient rat model was constructed and multi-colony-derived DPSCs were obtained from the incisors of ovariectomized (OVX) or sham-operated rats. Odonto/osteogenic differentiation and the possible involvement of the nuclear factor kappa B (NF-κB) pathway in the OVX-DPSCs/Sham-DPSCs of these rats were then investigated. OVX-DPSCs presented decreased odonto/osteogenic capacity and an activated NF-κB pathway, as compared with Sham-DPSCs. When the cellular NF-κB pathway was specifically inhibited by BMS345541, the odonto/osteogenic potential in OVX-DPSCs was significantly upregulated. Thus, estrogen deficiency down-regulated the odonto/osteogenic differentiation of DPSCs by activating NF-κB signaling and inhibition of the NF-κB pathway effectively rescued the decreased differentiation potential of DPSCs.
A dynamic systems engineering methodology research study. Phase 2: Evaluating methodologies, tools, and techniques for applicability to NASA's systems projects

NASA Technical Reports Server (NTRS)

Paul, Arthur S.; Gill, Tepper L.; Maclin, Arlene P.

1989-01-01

A study of NASA's Systems Management Policy (SMP) concluded that the primary methodology being used by the Mission Operations and Data Systems Directorate and its subordinate, the Networks Division, is very effective. Still some unmet needs were identified. This study involved evaluating methodologies, tools, and techniques with the potential for resolving the previously identified deficiencies. Six preselected methodologies being used by other organizations with similar development problems were studied. The study revealed a wide range of significant differences in structure. Each system had some strengths but none will satisfy all of the needs of the Networks Division. Areas for improvement of the methodology being used by the Networks Division are listed with recommendations for specific action.
The cultural parameters of lead poisoning: A medical anthropologist's view of intervention in environmental lead exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trotter, R.T. II

1990-11-01

This article identifies four culturally shaped sources of lead exposure in human societies: modern and historic technological sources; food habits; culturally defined health beliefs; and beauty practices. Examples of these potential sources of lead poisoning are presented from current cultures. They include the use of lead-glazed cooking pottery in Mexican-American households; folk medical use of lead in Hispanic, Arabic, South Asian, Chinese, and Hmong communities; as well as the use of lead as a cosmetic in the Near East, Southeast Asia, and South Asia. Four interacting cultural conditions that create barriers to the reduction of lead exposure and lead poisoningmore » are identified and discussed. These are knowledge deficiencies, communication resistance, cultural reinterpretations, and incongruity of explanatory models.« less

Stingray Failure Mode, Effects and Criticality Analysis: WEC Risk Registers

DOE Data Explorer

Ken Rhinefrank

2016-07-25

Analysis method to systematically identify all potential failure modes and their effects on the Stingray WEC system. This analysis is incorporated early in the development cycle such that the mitigation of the identified failure modes can be achieved cost effectively and efficiently. The FMECA can begin once there is enough detail to functions and failure modes of a given system, and its interfaces with other systems. The FMECA occurs coincidently with the design process and is an iterative process which allows for design changes to overcome deficiencies in the analysis.Risk Registers for major subsystems completed according to the methodology described in "Failure Mode Effects and Criticality Analysis Risk Reduction Program Plan.pdf" document below, in compliance with the DOE Risk Management Framework developed by NREL.
Diagnosing Lysosomal Storage Disorders: The GM2 Gangliosidoses.

PubMed

Hall, Patricia; Minnich, Sara; Teigen, Claire; Raymond, Kimiyo

2014-10-01

The GM2 gangliosidoses are a group of autosomal recessive lysosomal storage disorders caused by defective β-hexosaminidase. There are three clinical conditions in this group: Tay-Sachs disease (TSD), Sandhoff disease (SD), and hexosaminidase activator deficiency. The three conditions are clinically indistinguishable. TSD and SD have been identified with infantile, juvenile, and adult onset forms. The activator deficiency is only known to present with infantile onset. Diagnosis of TSD and SD is based on decreased hexosaminidase activity and a change in the percentage of activity between isoforms. There are no biochemical tests currently available for activator deficiency. This unit provides a detailed procedure for identifying TSD and SD in affected individuals and carriers from leukocyte samples, the most robust sample type available. Copyright © 2014 John Wiley & Sons, Inc.
Electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure.

PubMed

Fan, Ling; Chen, Li-Feng; Fan, Jing

2017-12-01

To investigate the electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure. Guinea pigs model of iron deficiency anemia complicated with chronic heart failure in 10 guinea pigs of the experimental group was made by feeding a low iron diet, pure water and subcutaneous injection of isoproterenol. The control group consisting of 11 guinea pigs was given normal food, normal water and injected with normal saline. The left ventricular outflow tract model specimen was also prepared. The standard microelectrode technique was used to observe electrophysiological changes of autonomic cells in the outflow tract of left ventricular heart failure complicated with iron deficiency anemia in guinea pig model. The indicators of observation were maximal diastolic potential, action potential amplitude, 0 phase maximal depolarization velocity, 4 phase automatic depolarization velocity, repolarization 50% and 90%, and spontaneous discharge frequency. Compared with the control group, 4 phase automatic depolarization velocity, spontaneous discharge frequency and 0 phase maximal depolarization velocity decreased significantly (P < 0.01) and action potential amplitude reduced (P < 0.01) in model group. Moreover, repolarization 50% and 90% increased (P < 0.01). There are electrophysiological abnormalities of the left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with heart failure. Copyright © 2017 Hainan Medical University. Production and hosting by Elsevier B.V. All rights reserved.
Aβ Damages Learning and Memory in Alzheimer's Disease Rats with Kidney-Yang Deficiency

PubMed Central

Qi, Dongmei; Qiao, Yongfa; Zhang, Xin; Yu, Huijuan; Cheng, Bin; Qiao, Haifa

2012-01-01

Previous studies demonstrated that Alzheimer's disease was considered as the consequence produced by deficiency of Kidney essence. However, the mechanism underlying the symptoms also remains elusive. Here we report that spatial learning and memory, escape, and swimming capacities were damaged significantly in Kidney-yang deficiency rats. Indeed, both hippocampal Aβ 40 and 42 increases in Kidney-yang deficiency contribute to the learning and memory impairments. Specifically, damage of synaptic plasticity is involved in the learning and memory impairment of Kidney-yang deficiency rats. We determined that the learning and memory damage in Kidney-yang deficiency due to synaptic plasticity impairment and increases of Aβ 40 and 42 was not caused via NMDA receptor internalization induced by Aβ increase. β-Adrenergic receptor agonist can rescue the impaired long-term potential (LTP) in Kidney-yang rats. Taken together, our results suggest that spatial learning and memory inhibited in Kidney-yang deficiency might be induced by Aβ increase and the decrease of β 2 receptor function in glia. PMID:22645624
Insights into the diagnosis and management of iron deficiency in inflammatory bowel disease.

PubMed

Bou-Fakhredin, Rayan; Halawi, Racha; Roumi, Joseph; Taher, Ali

2017-09-01

Iron deficiency is a frequent comorbidity of chronic diseases such as inflammatory bowel disease that can severely impact the health and quality of life of affected individuals. It can exist as a silent condition and manifest in non-specific symptoms even in the absence of anemia. Even though iron deficiency anemia is the most common complication and extra-intestinal manifestation of inflammatory bowel disease, the majority of inflammatory bowel disease patients who are diagnosed with iron deficiency anemia are not treated. Areas covered: In this review, we discuss iron deficiency and iron deficiency anemia in patients with inflammatory bowel disease, and review diagnostic and therapeutic options. Expert commentary: We invite international gastroenterological societies and associations to refine the practice guidelines and include iron deficiency as a potential morbidity associated with IBD in analogy to arthritis, uveitis or any other extra intestinal manifestations. There should a more unanimous agreement among different societies on the specific diagnostic cutoff values for C-reactive protein levels, serum ferritin, and transferrin saturation in order to differentiate iron deficiency anemia from anemia of chronic disease.
A novel KAL1 mutation is associated with combined pituitary hormone deficiency

PubMed Central

Takagi, Masaki; Narumi, Satoshi; Hamada, Riku; Hasegawa, Yukihiro; Hasegawa, Tomonobu

2014-01-01

Using a next-generation sequencing strategy, we identified a novel KAL1 missense mutation (p.His568Gln) in a patient with combined pituitary hormone deficiency, right microphthalmia, right renal aplasia and severe developmental delay. Our findings will provide additional evidence that KAL1 mutations are associated with hypopituitarism, in addition to luteinizing hormone, and follicle-stimulating hormone deficiencies, and improve our understanding of the phenotypic features and developmental course associated with KAL1 mutations. PMID:27081504
Using Color and Grayscale Images to Teach Histology to Color-Deficient Medical Students

ERIC Educational Resources Information Center

Rubin, Lindsay R.; Lackey, Wendy L.; Kennedy, Frances A.; Stephenson, Robert B.

2009-01-01

Examination of histologic and histopathologic microscopic sections relies upon differential colors provided by staining techniques, such as hematoxylin and eosin, to delineate normal tissue components and to identify pathologic alterations in these components. Given the prevalence of color deficiency (commonly called "color blindness")…
Effects of Deficient Reporting on Meta-Analysis: A Conceptual Framework and Reanalysis

ERIC Educational Resources Information Center

Orwin, Robert G.; Cordray, David S.

1985-01-01

Identifies three sources of reporting deficiency for meta-analytic results: quality (adequacy) of publicizing; quality of macrolevel reporting, and quality of microlevel reporting. Reanalysis of 25 reports from the Smith, Glass and Miller (1980) psychotherapy meta-analysis established two sources of misinformation, interrater reliabilities and…
Death talk: Basic linguistic rules and communication in perinatal and paediatric end-of-life discussions.

PubMed

Xafis, Vicki; Watkins, Andrew; Wilkinson, Dominic

2016-04-01

This paper considers clinician/parent communication difficulties noted by parents involved in end-of-life decision-making in the light of linguistic theory. Grice's Cooperative Principle and associated maxims, which enable effective communication, are examined in relation to communication deficiencies that parents have identified when making end-of-life decisions for the child. Examples from the literature are provided to clarify the impact of failing to observe the maxims on parents and on clinician/parent communication. Linguistic theory applied to the literature on parental concerns about clinician/parent communication shows that the violation of the maxims of quantity, quality, relation, and manner as well as the stance that some clinicians adopt during discussions with parents impact on clinician/parent communication and lead to distrust, anger, sadness, and long-term difficulties coping with the experience of losing one's child. Parents have identified communication deficiencies in end-of-life discussions. Relating these communication deficiencies to linguistic theory provides insight into communication difficulties but also solutions. Gaining an understanding of basic linguistic theory that underlies human interactions, gaining insight into the communication deficiencies that parents have identified, and modifying some communication behaviours in light of these with the suggestions made in this article may lead to improved clinician/parent communication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Toward reassessing data-deficient species.

PubMed

Bland, Lucie M; Bielby, Jon; Kearney, Stephen; Orme, C David L; Watson, James E M; Collen, Ben

2017-06-01

One in 6 species (13,465 species) on the International Union for Conservation of Nature (IUCN) Red List is classified as data deficient due to lack of information on their taxonomy, population status, or impact of threats. Despite the chance that many are at high risk of extinction, data-deficient species are typically excluded from global and local conservation priorities, as well as funding schemes. The number of data-deficient species will greatly increase as the IUCN Red List becomes more inclusive of poorly known and speciose groups. A strategic approach is urgently needed to enhance the conservation value of data-deficient assessments. To develop this, we reviewed 2879 data-deficient assessments in 6 animal groups and identified 8 main justifications for assigning data-deficient status (type series, few records, old records, uncertain provenance, uncertain population status or distribution, uncertain threats, taxonomic uncertainty, and new species). Assigning a consistent set of justification tags (i.e., consistent assignment to assessment justifications) to species classified as data deficient is a simple way to achieve more strategic assessments. Such tags would clarify the causes of data deficiency; facilitate the prediction of extinction risk; facilitate comparisons of data deficiency among taxonomic groups; and help prioritize species for reassessment. With renewed efforts, it could be straightforward to prevent thousands of data-deficient species slipping unnoticed toward extinction. © 2016 Society for Conservation Biology.
Chimeric protein identification of dystrophic, Pierson and other laminin polymerization residues

PubMed Central

McKee, Karen K.; Aleksandrova, Maya; Yurchenco, Peter D.

2018-01-01

Laminin polymerization is a key step of basement membrane self-assembly that depends on the binding of the three different N-terminal globular LN domains. Several mutations in the LN domains cause LAMA2-deficient muscular dystrophy and LAMB2-deficient Pierson syndrome. These mutations may affect polymerization. A novel approach to identify the amino acid residues required for polymerization has been applied to an analysis of these and other laminin LN mutations. The approach utilizes laminin-nidogen chimeric fusion proteins that bind to recombinant non-polymerizing laminins to provide a missing functional LN domain. Single amino acid substitutions introduced into these chimeras were tested to determine if polymerization activity and the ability to assemble on cell surfaces were lost. Several laminin-deficient muscular dystrophy mutations, renal Pierson syndrome mutations, and Drosophila mutations causing defects of heart development were identified as ones causing loss of laminin polymerization. In addition, two novel residues required for polymerization were identified in the laminin γ1 LN domain. PMID:29408412
Thiamin deficiency in people with obesity.

PubMed

Kerns, Jennifer C; Arundel, Cherinne; Chawla, Lakhmir S

2015-03-01

Although obesity has been viewed traditionally as a disease of excess nutrition, evidence suggests that it may also be a disease of malnutrition. Specifically, thiamin deficiency was found in 15.5-29% of obese patients seeking bariatric surgery. It can present with vague signs and symptoms and is often overlooked in patients without alcohol use disorders. This review explores the relatively new discovery of high rates of thiamin deficiency in certain populations of people with obesity, including the effects of thiamin deficiency and potential underlying mechanisms of deficiency in people with obesity. The 2 observational studies that examined the prevalence in preoperative bariatric surgery patients and gaps in our current knowledge (including the prevalence of thiamin deficiency in the general obese population and whether the current RDA for thiamin meets the metabolic needs of overweight or obese adults) are reviewed. Suggestions for future areas of research are included. © 2015 American Society for Nutrition.
Hypopituitarism: growth hormone and corticotropin deficiency.

PubMed

Capatina, Cristina; Wass, John A H

2015-03-01

This article presents an overview of adult growth hormone deficiency (AGHD) and corticotropin deficiency (central adrenal failure, CAI). Both conditions can result from various ailments affecting the hypothalamus or pituitary gland (most frequently a tumor in the area or its treatment). Clinical manifestations are subtle in AGHD but potentially life-threatening in CAI. The diagnosis needs dynamic testing in most cases. Treatment of AGHD is recommended in patients with documented severe deficiency, and treatment of CAI is mandatory in all cases. Despite significant progress in replacement hormonal therapy, more physiologic treatments and more reliable indicators of treatment adequacy are still needed. Copyright © 2015 Elsevier Inc. All rights reserved.
Severe hypophosphataemia after intravenous iron administration.

PubMed

Anand, Gurpreet; Schmid, Christoph

2017-03-13

Iron deficiency is common and can be effectively treated with parenteral iron infusion. We report a case of an iron-deficient and vitamin D-deficient woman who developed severe symptomatic hypophosphataemia following intravenous ferric carboxymaltose administration. We stress the need of increased awareness of this potential complication among physicians. Patients should be informed of this complication and instructed to report for follow-up if they experience new musculoskeletal symptoms or worsening of tiredness. As severe hypophosphataemia is usually symptomatic, we recommend screening symptomatic patients for this complication. Recognising and treating the possible exacerbating factors, especially vitamin D deficiency, might be a simple measure to mitigate this complication. 2017 BMJ Publishing Group Ltd.
Severe hypophosphataemia after intravenous iron administration

PubMed Central

Anand, Gurpreet; Schmid, Christoph

2017-01-01

Iron deficiency is common and can be effectively treated with parenteral iron infusion. We report a case of an iron-deficient and vitamin D-deficient woman who developed severe symptomatic hypophosphataemia following intravenous ferric carboxymaltose administration. We stress the need of increased awareness of this potential complication among physicians. Patients should be informed of this complication and instructed to report for follow-up if they experience new musculoskeletal symptoms or worsening of tiredness. As severe hypophosphataemia is usually symptomatic, we recommend screening symptomatic patients for this complication. Recognising and treating the possible exacerbating factors, especially vitamin D deficiency, might be a simple measure to mitigate this complication. PMID:28289000
Where is industry getting it wrong? A review of quality concerns raised at Day 120 by the Committee For Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products.

PubMed

Borg, John Joseph; Robert, Jean-Louis; Wade, George; Aislaitner, George; Pirozynski, Michal; Abadie, Eric; Salmonson, Tomas; Vella Bonanno, Patricia

2009-01-01

The aim of this study was to identify common trends in the deficiencies identified in the quality part of the dossier during the evaluation of marketing authorisation applications for medicinal products for human use submitted through the EU's centralised procedure. We analysed all the adopted Day 120 list of questions on the quality module of 52 marketing authorisation applications for chemical entity medicinal products submitted to the European Medicines Agency and evaluated by the Committee for Medicinal Products for Human Use (CHMP), during 12 consecutive plenary meetings held in 2007 and 2008. Subsequently we calculated the frequency of common deficiencies identified across these applications. Frequencies and trends on quality deficiencies have been recorded and presented for 52 marketing authorisation applications. 32 "Major Objections" originated from 13 marketing authorisation applications. 13 concerned were raised regarding drug substances and 19 for drug products. Furthermore, 905 concerns on drug substance and 1,054 on drug product were also adopted. The impact of the frequencies and trends in quality deficiencies that were identified are discussed from a regulatory point of view. It is expected that the results of this study will not only be of interest to pharmaceutical companies but will also aid regulators' in obtaining consistent information on drug products based on transparent rules safeguarding the necessary pharmaceutical quality of medicinal products.
Cardiac structural changes and electrical remodeling in a thiamine-deficiency model in rats.

PubMed

Roman-Campos, D; Campos, A C; Gioda, C R; Campos, P P; Medeiros, M A A; Cruz, J S

2009-06-05

Thiamine is an important cofactor present in many biochemical reactions, and its deprivation can lead to heart dysfunction. Little is known about the influence of thiamine deprivation on the electrophysiological behavior of the isolated heart cells and information about thiamine deficiency in heart morphology is controversial. Thus, we decided to investigate the major repolarizing conductances and their influence in the action potential (AP) waveform as well as the changes in the heart structure in a set of thiamine deficiency in rats. Using the patch-clamp technique, we investigated inward (I(K1)) and outward K(+) currents (I(to)), T-type and L-type Ca(2+) currents and APs. To evaluate heart morphology we used hematoxylin and eosin in transversal heart sections. Thiamine deficiency caused a marked decrease in left ventricle thickness, cardiomyocyte number, cell length and width, and membrane capacitance. When evaluating I(to) we did not find difference in current amplitude; however an acceleration of I(to) inactivation was observed. I(K1) showed a reduction in the amplitude and slope conductance, which implicated a less negative resting membrane potential in cardiac myocytes isolated from thiamine-deficient rats. We did not find any difference in L-type Ca(2+) current density. T-type Ca(2+) current was not observed. In addition, we did not observe significant changes in AP repolarization. Based on our study we can conclude that thiamine deficiency causes heart hypotrophy and not heart hypertrophy. Moreover, we provided evidence that there is no major electrical remodeling during thiamine deficiency, a feature of heart failure models.
Astrocyte dysfunction following molybdenum-associated purine loading could initiate Parkinson's disease with dementia.

PubMed

Bourke, Christopher A

2018-01-01

Sporadic or idiopathic Parkinson's disease is a movement disorder with a worldwide distribution, a long pre-clinical latent period and a frequent association with dementia. The combination of molybdenum deficiency and purine ingestion could explain the movement disorder, the distribution, the latent period and the dementia association. Recent studies in sheep have shown that molybdenum deficiency enables some dietary purines to accumulate in the central nervous system. This causes astrocyte dysfunction, altered neuromodulation and eventually irreversible central nervous system disease. Humans and sheep share the ability to salvage purines and this ability places humans at risk when they ingest xanthosine, inosine, adenosine and guanosine. Adenosine ingestion in molybdenum-deficient humans will lead to adenosine loading and potentially a disturbance to the A2a adenosine receptors in the nigro-striatum. This could result in Parkinson's disease. Guanosine ingestion in molybdenum-deficient humans will lead to guanosine loading and potentially a disturbance to the guanosine receptors in the hippocampus, amygdala and ventral striatum. This could result in dementia. The molybdenum content of the average daily diet in the United States is 0.07 ppm and in the United Kingdom 0.04 ppm. Central nervous system disease occurs in sheep at <0.04 ppm. Consistent with the role proposed for molybdenum deficiency in Parkinson's disease is the observation that affected individuals have elevated sulfur amino acid levels, depressed sulfate levels, and depressed uric acid levels. Likewise the geographical distribution of Parkinson's dementia complex on Guam corresponds with the distribution of molybdenum-deficient soils hence molybdenum-deficient food gardens on that island.
Antimalarial NADPH-Consuming Redox-Cyclers As Superior Glucose-6-Phosphate Dehydrogenase Deficiency Copycats.

PubMed

Bielitza, Max; Belorgey, Didier; Ehrhardt, Katharina; Johann, Laure; Lanfranchi, Don Antoine; Gallo, Valentina; Schwarzer, Evelin; Mohring, Franziska; Jortzik, Esther; Williams, David L; Becker, Katja; Arese, Paolo; Elhabiri, Mourad; Davioud-Charvet, Elisabeth

2015-05-20

Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum were shown to protect G6PD-deficient populations from severe malaria. Here, we investigated the mechanism of a novel antimalarial series, namely 3-[substituted-benzyl]-menadiones, to understand whether these NADPH-consuming redox-cyclers, which induce oxidative stress, mimic the natural protection of G6PD deficiency. We demonstrated that the key benzoylmenadione metabolite of the lead compound acts as an efficient redox-cycler in NADPH-dependent methaemoglobin reduction, leading to the continuous formation of reactive oxygen species, ferrylhaemoglobin, and subsequent haemichrome precipitation. Structure-activity relationships evidenced that both drug metabolites and haemoglobin catabolites contribute to potentiate drug effects and inhibit parasite development. Disruption of redox homeostasis by the lead benzylmenadione was specifically induced in Plasmodium falciparum parasitized erythrocytes and not in non-infected cells, and was visualized via changes in the glutathione redox potential of living parasite cytosols. Furthermore, the redox-cycler shows additive and synergistic effects in combination with compounds affecting the NADPH flux in vivo. The lead benzylmenadione 1c is the first example of a novel redox-active agent that mimics the behavior of a falciparum parasite developing inside a G6PD-deficient red blood cell (RBC) giving rise to malaria protection, and it exerts specific additive effects that are inhibitory to parasite development, without harm for non-infected G6PD-sufficient or -deficient RBCs. This strategy offers an innovative perspective for the development of future antimalarial drugs for G6PD-sufficient and -deficient populations.
Characterization of Dysferlin Deficient SJL/J Mice to Assess Preclinical Drug Efficacy: Fasudil Exacerbates Muscle Disease Phenotype

PubMed Central

Rayavarapu, Sree; Van der meulen, Jack H.; Gordish-Dressman, Heather; Hoffman, Eric P.; Nagaraju, Kanneboyina; Knoblach, Susan M.

2010-01-01

The dysferlin deficient SJL/J mouse strain is commonly used to study dysferlin deficient myopathies. Therefore, we systematically evaluated behavior in relatively young (9–25 weeks) SJL/J mice and compared them to C57BL6 mice to determine which functional end points may be the most effective to use for preclinical studies in the SJL/J strain. SJL/J mice had reduced body weight, lower open field scores, higher creatine kinase levels, and less muscle force than did C57BL6 mice. Power calculations for expected effect sizes indicated that grip strength normalized to body weight and open field activity were the most sensitive indicators of functional status in SJL/J mice. Weight and open field scores of SJL/J mice deteriorated over the course of the study, indicating that progressive myopathy was ongoing even in relatively young (<6 months old) SJL/J mice. To further characterize SJL/J mice within the context of treatment, we assessed the effect of fasudil, a rho-kinase inhibitor, on disease phenotype. Fasudil was evaluated based on previous observations that Rho signaling may be overly activated as part of the inflammatory cascade in SJL/J mice. Fasudil treated SJL/J mice showed increased body weight, but decreased grip strength, horizontal activity, and soleus muscle force, compared to untreated SJL/J controls. Fasudil either improved or had no effect on these outcomes in C57BL6 mice. Fasudil also reduced the number of infiltrating macrophages/monocytes in SJL/J muscle tissue, but had no effect on muscle fiber degeneration/regeneration. These studies provide a basis for standardization of preclinical drug testing trials in the dysferlin deficient SJL/J mice, and identify measures of functional status that are potentially translatable to clinical trial outcomes. In addition, the data provide pharmacological evidence suggesting that activation of rho-kinase, at least in part, may represent a beneficial compensatory response in dysferlin deficient myopathies. PMID:20886045

Body size, extinction risk and knowledge bias in New World snakes.

PubMed

Vilela, Bruno; Villalobos, Fabricio; Rodríguez, Miguel Ángel; Terribile, Levi Carina

2014-01-01

Extinction risk and body size have been found to be related in various vertebrate groups, with larger species being more at risk than smaller ones. We checked whether this was also the case for snakes by investigating extinction risk-body size relationships in the New World's Colubroidea species. We used the IUCN Red List risk categories to assign each species to one of two broad levels of threat (Threatened and Non-Threatened) or to identify it as either Data Deficient or Not-Evaluated by the IUCN. We also included the year of description of each species in our analysis as this could affect the level of threat assigned to it (earlier described species had more time to gather information about them, which might have facilitated their evaluation). Also, species detectability could be a function of body size, with larger species tending to be described earlier, which could have an impact in extinction risk-body size relationships. We found a negative relationship between body size and description year, with large-bodied species being described earlier. Description year also varied among risk categories, with Non-Threatened species being described earlier than Threatened species and both species groups earlier than Data Deficient species. On average, Data Deficient species also presented smaller body sizes, while no size differences were detected between Threatened and Non-Threatened species. So it seems that smaller body sizes are related with species detectability, thus potentially affecting both when a species is described (smaller species tend to be described more recently) as well as the amount of information gathered about it (Data Deficient species tend to be smaller). Our data also indicated that if Data Deficient species were to be categorized as Threatened in the future, snake body size and extinction risk would be negatively related, contrasting with the opposite pattern commonly observed in other vertebrate groups.
Body Size, Extinction Risk and Knowledge Bias in New World Snakes

PubMed Central

Vilela, Bruno; Villalobos, Fabricio; Rodríguez, Miguel Ángel; Terribile, Levi Carina

2014-01-01

Extinction risk and body size have been found to be related in various vertebrate groups, with larger species being more at risk than smaller ones. We checked whether this was also the case for snakes by investigating extinction risk–body size relationships in the New World's Colubroidea species. We used the IUCN Red List risk categories to assign each species to one of two broad levels of threat (Threatened and Non-Threatened) or to identify it as either Data Deficient or Not-Evaluated by the IUCN. We also included the year of description of each species in our analysis as this could affect the level of threat assigned to it (earlier described species had more time to gather information about them, which might have facilitated their evaluation). Also, species detectability could be a function of body size, with larger species tending to be described earlier, which could have an impact in extinction risk–body size relationships. We found a negative relationship between body size and description year, with large-bodied species being described earlier. Description year also varied among risk categories, with Non-Threatened species being described earlier than Threatened species and both species groups earlier than Data Deficient species. On average, Data Deficient species also presented smaller body sizes, while no size differences were detected between Threatened and Non-Threatened species. So it seems that smaller body sizes are related with species detectability, thus potentially affecting both when a species is described (smaller species tend to be described more recently) as well as the amount of information gathered about it (Data Deficient species tend to be smaller). Our data also indicated that if Data Deficient species were to be categorized as Threatened in the future, snake body size and extinction risk would be negatively related, contrasting with the opposite pattern commonly observed in other vertebrate groups. PMID:25409293
An update on the association of vitamin D deficiency with common infectious diseases.

PubMed

Watkins, Richard R; Lemonovich, Tracy L; Salata, Robert A

2015-05-01

Vitamin D plays an important role in modulating the immune response to infections. Deficiency of vitamin D is a common condition, affecting both the general population and patients in health care facilities. Over the last decade, an increasing body of evidence has shown an association between vitamin D deficiency and an increased risk for acquiring several infectious diseases, as well as poorer outcomes in vitamin D deficient patients with infections. This review details recent developments in understanding the role of vitamin D in immunity, the antibacterial actions of vitamin D, the association between vitamin D deficiency and common infections (like sepsis, pneumonia, influenza, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus type-1 (HIV), and hepatitis C virus (HCV)), potential therapeutic implications for vitamin D replacement, and future research directions.
A Systems Approach to Evaluating Ionizing Radiation: Six Focus Areas to Improve Quality, Efficiency, and Patient Safety

PubMed Central

Mower, Laura; Bushe, Chris

2015-01-01

Abstract: Ionizing radiation is an essential component of the care process. However, providers and patients may not be fully aware of the risks involved, the level of ionizing radiation delivered with various procedures, or the potential for harm through incidental overexposure or cumulative dose. Recent high-profile incidents demonstrating the devastating short-term consequences of radiation overexposure have drawn attention to these risks, but applicable solutions are lacking. Although various recommendations and guidelines have been proposed, organizational variability challenges providers to identify their own practical solutions. To identify potential failure modes and develop solutions to preserve patient safety within a large, national healthcare system, we assembled a multidisciplinary team to conduct a comprehensive analysis of practices surrounding the delivery of ionizing radiation. Workgroups were developed to analyze existing culture, processes, and technology to identify deficiencies and propose solutions. Six focus areas were identified: competency and certification; equipment; monitoring and auditing; education; clinical pathways; and communication and marketing. This manuscript summarizes this comprehensive, multidisciplinary, and systemic analysis of risk and provides examples to illustrate how these focus areas can be used to improve the use of ionizing radiation. The proposed solutions, once fully implemented, may advance patient safety and care. PMID:26042626
Developing Hypothetical Inhibition Mechanism of Novel Urea Transporter B Inhibitor

NASA Astrophysics Data System (ADS)

Li, Min; Tou, Weng Ieong; Zhou, Hong; Li, Fei; Ren, Huiwen; Chen, Calvin Yu-Chian; Yang, Baoxue

2014-07-01

Urea transporter B (UT-B) is a membrane channel protein that specifically transports urea. UT-B null mouse exhibited urea selective urine concentrating ability deficiency, which suggests the potential clinical applications of the UT-B inhibitors as novel diuretics. Primary high-throughput virtual screening (HTVS) of 50000 small-molecular drug-like compounds identified 2319 hit compounds. These 2319 compounds were screened by high-throughput screening using an erythrocyte osmotic lysis assay. Based on the pharmacological data, putative UT-B binding sites were identified by structure-based drug design and validated by ligand-based and QSAR model. Additionally, UT-B structural and functional characteristics under inhibitors treated and untreated conditions were simulated by molecular dynamics (MD). As the result, we identified four classes of compounds with UT-B inhibitory activity and predicted a human UT-B model, based on which computative binding sites were identified and validated. A novel potential mechanism of UT-B inhibitory activity was discovered by comparing UT-B from different species. Results suggest residue PHE198 in rat and mouse UT-B might block the inhibitor migration pathway. Inhibitory mechanisms of UT-B inhibitors and the functions of key residues in UT-B were proposed. The binding site analysis provides a structural basis for lead identification and optimization of UT-B inhibitors.
Congenital hypogonadotropic hypogonadism: implications of absent mini-puberty.

PubMed

Dwyer, Andrew A; Jayasena, Channa N; Quinton, Richard

2016-06-01

The phenomenon known as "mini-puberty" refers to activation of the neonatal hypothalamo-pituitary axis causing serum concentrations of gonadotrophins and testosterone (T) to approach adult male levels. This early neonatal period is a key proliferative window for testicular germ cells and immature Sertoli cells. Although failure to spontaneously initiate (adolescent) puberty is the most evident consequence of a defective gonadotropin-releasing hormone (GnRH) neurosecretory network, absent mini-puberty is also likely to have a major impact on the reproductive phenotype of men with congenital hypogonadotrophic hypogonadism (CHH). Furthermore, the phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency (either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood. Among male neonates exhibiting "red flag" indicators for CHH (i.e. maldescended testes with or without cryptorchidism) a single serum sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and with much greater accuracy than dynamic tests performed in later childhood or adolescence. Potential consequences for missing absent mini-puberty in a male neonate include the lack of monitoring of pubertal progression/lack of progression, and the missed opportunity for early therapeutic intervention. This article will review our current understanding of the mechanisms and clinical consequences of mini-puberty. Furthermore, evidence for the optimal clinical management of patients with absent mini-puberty will be discussed.
Status of selected nutrients in obese dogs undergoing caloric restriction.

PubMed

Linder, Deborah E; Freeman, Lisa M; Holden, Shelley L; Biourge, Vincent; German, Alexander J

2013-10-24

The purpose of this study was to test the hypothesis that dog plasma concentrations of selected nutrients decrease after undergoing caloric restriction for weight loss. Thirty-one overweight dogs that had successfully lost at least 15% of initial body weight were included in the study. Nutrients that had been previously identified to be at potential risk of deficiency during caloric restriction were measured in plasma (choline, amino acids) and urine (selenium) at the initiation and completion of a standardized weight loss regimen in dogs. Dogs remained healthy throughout the study, and no signs attributable to nutrient deficiency were noted. Percentage weight loss was 28.3% (16.0-40.1%) starting body weight, over a period of 250 days (91-674 days). Median energy intake during the weight loss period was 62 (44 to 74) Kcal/kg(0.75) target weight per day. Choline (P = 0.046) and threonine (P = 0.02) decreased after weight loss. Glycine (P = 0.041), and urinary selenium:creatinine ratio (P = 0.006) both increased after weight loss. There were no other significant differences in plasma nutrient concentrations. Since concentrations of most measured nutrients did not change significantly, the data are not consistent with widespread nutrient deficiency in dogs undergoing caloric restriction using a diet formulated for weight loss. However, the significance of the decrease in plasma choline concentration requires further assessment.
Anemia among Children Exposed to Polyparasitism in Coastal Kenya

PubMed Central

Cojulun, Alicia Chang; Bustinduy, Amaya L.; Sutherland, Laura J.; Mungai, Peter L.; Mutuku, Francis; Muchiri, Eric; Kitron, Uriel; King, Charles H.

2015-01-01

Anemia represents a substantial problem for children living in areas with limited resources and significant parasite burden. We performed a cross-sectional study of 254 Kenyan preschool- and early school-age children in a setting endemic for multiple chronic parasitic infections to explore mechanisms of their anemia. Complete venous blood cell counts revealed a high prevalence of local childhood anemia (79%). Evaluating the potential links between low hemoglobin and socioeconomic factors, nutritional status, hemoglobinopathy, and/or parasite infection, we identified age < 9 years (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 4.4, 33) and the presence of asymptomatic malaria infection (OR: 6.8, 95% CI: 2.1, 22) as the strongest independent correlates of having anemia. A total of 130/155 (84%) of anemic children with iron studies had evidence of iron-deficiency anemia (IDA), 16% had non-IDA; 50/52 of additionally tested anemic children met soluble transferrin-receptor (sTfR) criteria for combined anemia of inflammation (AI) with IDA. Children in the youngest age group had the greatest odds of iron deficiency (OR: 10.0, 95% CI: 3.9, 26). Although older children aged 9–11 years had less anemia, they had more detectable malaria, Schistosoma infection, hookworm, and proportionately more non-IDA. Anemia in this setting appears multifactorial such that chronic inflammation and iron deficiency need to be addressed together as part of integrated management of childhood anemia. PMID:26324733
Matricellular protein CCN3 mitigates abdominal aortic aneurysm

PubMed Central

Zhang, Chao; van der Voort, Dustin; Shi, Hong; Qing, Yulan; Hiraoka, Shuichi; Takemoto, Minoru; Yokote, Koutaro; Moxon, Joseph V.; Norman, Paul; Rittié, Laure; Atkins, G. Brandon; Gerson, Stanton L.; Shi, Guo-Ping; Golledge, Jonathan; Dong, Nianguo; Perbal, Bernard; Prosdocimo, Domenick A.

2016-01-01

Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II–induced AAA and elastase perfusion–stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II–induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease. PMID:26974158
Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?

PubMed

Horvath, Gabriella A; Demos, Michelle; Shyr, Casper; Matthews, Allison; Zhang, Linhua; Race, Simone; Stockler-Ipsiroglu, Sylvia; Van Allen, Margot I; Mancarci, Ogan; Toker, Lilah; Pavlidis, Paul; Ross, Colin J; Wasserman, Wyeth W; Trump, Natalie; Heales, Simon; Pope, Simon; Cross, J Helen; van Karnebeek, Clara D M

2016-01-01

We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy and cerebral/cerebellar atrophy. In the cerebrospinal fluid both homovanillic acid and 5-hydroxyindoleacetic acid were significantly decreased; extensive biochemical and genetic investigations ruled out primary neurotransmitter deficiencies and other known inborn errors of metabolism. In an 8-year old female with an early onset intractable epileptic encephalopathy, developmental regression, and progressive cerebellar atrophy, a previously unreported de novo missense mutation was identified in SCN8A (c.5615G>A; p.Arg1872Gln), affecting a highly conserved residue located in the C-terminal of the Nav1.6 protein. Aside from decreased homovanillic acid and 5-hydroxyindoleacetic acid, 5-methyltetrahydrofolate was also found to be low. We hypothesize that these channelopathies cause abnormal synaptic mono-amine metabolite secretion/uptake via impaired vesicular release and imbalance in electrochemical ion gradients, which in turn aggravate the seizures. Treatment with oral 5-hydroxytryptophan, l-Dopa/Carbidopa, and a dopa agonist resulted in mild improvement of seizure control in the male case, most likely via dopamine and serotonin receptor activated signal transduction and modulation of glutamatergic, GABA-ergic and glycinergic neurotransmission. Neurotransmitter analysis in other sodium channelopathy patients will help validate our findings, potentially yielding novel treatment opportunities. Copyright © 2015 Elsevier Inc. All rights reserved.
Mild and moderate Mannose Binding Lectin deficiency are associated with systemic lupus erythematosus and lupus nephritis in Brazilian patients.

PubMed

Perazzio, Sandro Félix; Silva, Neusa Pereira da; Carneiro-Sampaio, Magda; Andrade, Luis Eduardo Coelho

2016-01-01

The potential association of mannose binding lectin (MBL) deficiency and systemic lupus erythematosus (SLE) has been investigated in several studies, but results have been mixed. One explanation for the conflicting results could be differences in ethnic background of study subjects. In this study we investigated the association of MBL deficiency and SLE in a large cohort of Brazilian SLE patients and controls. Serum MBL and Complement levels were determined for 286 Brazilian adult SLE patients and 301 healthy Brazilian adults as controls. MBL deficiency was classified as mild (<1000 and ≥500μg/L), moderate (<500 and ≥100μg/L) or severe (<100μg/L). SLE patients presented higher frequency of mild and moderate MBL deficiency compared to controls. SLE patients with MBL deficiency presented higher frequency of lupus nephritis compared to those without MBL deficiency. MBL deficiency was not associated with any other clinical manifestation, use of immunosuppressant therapy, disease activity, disease severity serum or Complement levels. This study shows that an association between MBL deficiency and SLE does exist in the Brazilian population. We also found an association between MBL deficiency and lupus nephritis. These findings support the hypothesis that MBL deficiency contributes to the development of SLE and lupus nephritis. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.
RNA interference-mediated silencing of genes involved in the immune responses of the soybean pod borer Leguminivora glycinivorella (Lepidoptera: Olethreutidae).

PubMed

Ran, Ruixue; Li, Tianyu; Liu, Xinxin; Ni, Hejia; Li, Wenbin; Meng, Fanli

2018-01-01

RNA interference (RNAi) technology may be useful for developing new crop protection strategies against the soybean pod borer (SPB; Leguminivora glycinivorella ), which is a critical soybean pest in northeastern Asia. Immune-related genes have been recently identified as potential RNAi targets for controlling insects. However, little is known about these genes or mechanisms underlying their expression in the SPB. In this study, we completed a transcriptome-wide analysis of SPB immune-related genes. We identified 41 genes associated with SPB microbial recognition proteins, immune-related effectors or signalling molecules in immune response pathways (e.g., Toll and immune deficiency pathways). Eleven of these genes were selected for a double-stranded RNA artificial feeding assay. The down-regulated expression levels of LgToll-5-1a and LgPGRP-LB2a resulted in relatively high larval mortality rates and abnormal development. Our data represent a comprehensive genetic resource for immune-related SPB genes, and may contribute to the elucidation of the mechanism regulating innate immunity in Lepidoptera species. Furthermore, two immune-related SPB genes were identified as potential RNAi targets, which may be used in the development of RNAi-mediated SPB control methods.
RNA interference-mediated silencing of genes involved in the immune responses of the soybean pod borer Leguminivora glycinivorella (Lepidoptera: Olethreutidae)

PubMed Central

Ran, Ruixue; Li, Tianyu; Liu, Xinxin; Ni, Hejia; Li, Wenbin

2018-01-01

RNA interference (RNAi) technology may be useful for developing new crop protection strategies against the soybean pod borer (SPB; Leguminivora glycinivorella), which is a critical soybean pest in northeastern Asia. Immune-related genes have been recently identified as potential RNAi targets for controlling insects. However, little is known about these genes or mechanisms underlying their expression in the SPB. In this study, we completed a transcriptome-wide analysis of SPB immune-related genes. We identified 41 genes associated with SPB microbial recognition proteins, immune-related effectors or signalling molecules in immune response pathways (e.g., Toll and immune deficiency pathways). Eleven of these genes were selected for a double-stranded RNA artificial feeding assay. The down-regulated expression levels of LgToll-5-1a and LgPGRP-LB2a resulted in relatively high larval mortality rates and abnormal development. Our data represent a comprehensive genetic resource for immune-related SPB genes, and may contribute to the elucidation of the mechanism regulating innate immunity in Lepidoptera species. Furthermore, two immune-related SPB genes were identified as potential RNAi targets, which may be used in the development of RNAi-mediated SPB control methods. PMID:29910977
Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy.

PubMed

Andrès, Emmanuel; Vidal-Alaball, Josep; Federici, Laure; Loukili, Noureddine Henoun; Zimmer, Jacques; Kaltenbach, Georges

2007-10-01

The aim of this work was to review the literature concerning cobalamin deficiency in elderly patients. Articles were identified through searches of PubMed-MEDLINE (January 1990 to June 2006), restricted to: English and French language, human subjects, elderly patients (>65 years), clinical trial, review and guidelines. Additional unpublished data from our cohort with cobalamin deficiency at the University Hospital of Strasbourg, France, were also considered. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study. In elderly people, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. The recently identified food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or from its binding proteins. This syndrome is usually the consequence of atrophic gastritis, related or not to Helicobacter pylori infection, and of the long-term ingestion of antacids and biguanides (in around 60% of the patients). Management of cobalamin deficiency has been well established with the use of cobalamin injections. However, new routes of cobalamin administration (oral and nasal) are currently being developed, especially the use of oral cobalamin therapy to treat food-cobalamin malabsorption.
Genotype-Phenotype Correlation in Primary Carnitine Deficiency

PubMed Central

Rose, Emily Cornforth; di San Filippo, Cristina Amat; Ndukwe Erlingsson, Uzochi C.; Ardon, Orly; Pasquali, Marzia; Longo, Nicola

2011-01-01

Primary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women’s than in the symptomatic patients’ fibroblasts (p<0.01). By contrast, ergothioneine transport (a selective substrate of the OCTN1 transporter, tested here as a control) was similar in cells from controls and patients with carnitine deficiency. DNA sequencing indicated an increased frequency of nonsense mutations in symptomatic patients (p<0.001). Expression of the missense mutations in CHO cells indicated that many mutations retained residual carnitine transport activity, with no difference in the average activity of missense mutations identified in symptomatic versus asymptomatic patients. These results indicate that cells from asymptomatic women have on average higher levels of residual carnitine transport activity as compared to that of symptomatic patients due to the presence of at least one missense mutation. PMID:21922592
Clinical evaluation and mutational analysis of GALK and GALE genes in patients with galactosemia in Greece: one novel mutation and two rare cases.

PubMed

Schulpis, Kleopatra H; Thodi, Georgia; Iakovou, Konstantinos; Chatzidaki, Maria; Dotsikas, Yannis; Molou, Elina; Triantafylli, Olga; Loukas, Yannis L

2017-07-26

Deficiencies of galactokinase (GALK) and UDP-epimerase (GALE) are implicated with galactose metabolic disorders. The aim of the study was the identification of mutations in GALK and GALE genes and clinical evaluation of patients. Five patients with GALK and five with GALE deficiency were picked up via the Neonatal Screening Program. Additionally, two females, 4 years old, were referred with late diagnosed galactosemia, as rare cases. Mutational analysis was conducted via Sanger sequencing, while in silico analysis tools were utilized for the novel mutation. Psychomotor and speech development tests were performed, as well. The mutation p.Pro28Thr was identified in both alleles in GALK-deficient patients of Roma (gypsy) origin, whereas the novel p.Asn39Ser was detected in two non-Roma patients. In GALE-deficient patients benign and/or likely benign mutations were found. Psychomotor and speech delay were determined in the Roma GALK patients. In each of the late diagnosed females, four mutations were identified in all galactosemia-related genes. The mutational spectrums of GALE- and GALK-deficient patients in Greece are presented for the first time along with a clinical evaluation. Mutational analysis in all galactosemia-related genes of symptomatic patients is highly recommended for future cases.
The role of leptin in regulating bone metabolism

PubMed Central

Upadhyay, Jagriti; Farr, Olivia M.; Mantzoros, Christos S.

2015-01-01

Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature on indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk – benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals. PMID:25497343
The role of leptin in regulating bone metabolism.

PubMed

Upadhyay, Jagriti; Farr, Olivia M; Mantzoros, Christos S

2015-01-01

Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals. Copyright © 2015. Published by Elsevier Inc.
Transcriptome Sequencing Identifies SPL7-Regulated Copper Acquisition Genes FRO4/FRO5 and the Copper Dependence of Iron Homeostasis in Arabidopsis[C][W

PubMed Central

Bernal, María; Casero, David; Singh, Vasantika; Wilson, Grandon T.; Grande, Arne; Yang, Huijun; Dodani, Sheel C.; Pellegrini, Matteo; Huijser, Peter; Connolly, Erin L.; Merchant, Sabeeha S.; Krämer, Ute

2012-01-01

The transition metal copper (Cu) is essential for all living organisms but is toxic when present in excess. To identify Cu deficiency responses comprehensively, we conducted genome-wide sequencing-based transcript profiling of Arabidopsis thaliana wild-type plants and of a mutant defective in the gene encoding SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7), which acts as a transcriptional regulator of Cu deficiency responses. In response to Cu deficiency, FERRIC REDUCTASE OXIDASE5 (FRO5) and FRO4 transcript levels increased strongly, in an SPL7-dependent manner. Biochemical assays and confocal imaging of a Cu-specific fluorophore showed that high-affinity root Cu uptake requires prior FRO5/FRO4-dependent Cu(II)-specific reduction to Cu(I) and SPL7 function. Plant iron (Fe) deficiency markers were activated in Cu-deficient media, in which reduced growth of the spl7 mutant was partially rescued by Fe supplementation. Cultivation in Cu-deficient media caused a defect in root-to-shoot Fe translocation, which was exacerbated in spl7 and associated with a lack of ferroxidase activity. This is consistent with a possible role for a multicopper oxidase in Arabidopsis Fe homeostasis, as previously described in yeast, humans, and green algae. These insights into root Cu uptake and the interaction between Cu and Fe homeostasis will advance plant nutrition, crop breeding, and biogeochemical research. PMID:22374396
Glycosyltransferase Function in Core 2-Type Protein O Glycosylation▿

PubMed Central

Stone, Erica L.; Ismail, Mohd Nazri; Lee, Seung Ho; Luu, Ying; Ramirez, Kevin; Haslam, Stuart M.; Ho, Samuel B.; Dell, Anne; Fukuda, Minoru; Marth, Jamey D.

2009-01-01

Three glycosyltransferases have been identified in mammals that can initiate core 2 protein O glycosylation. Core 2 O-glycans are abundant among glycoproteins but, to date, few functions for these structures have been identified. To investigate the biological roles of core 2 O-glycans, we produced and characterized mice deficient in one or more of the three known glycosyltransferases that generate core 2 O-glycans (C2GnT1, C2GnT2, and C2GnT3). A role for C2GnT1 in selectin ligand formation has been described. We now report that C2GnT2 deficiency impaired the mucosal barrier and increased susceptibility to colitis. C2GnT2 deficiency also reduced immunoglobulin abundance and resulted in the loss of all core 4 O-glycan biosynthetic activity. In contrast, the absence of C2GnT3 altered behavior linked to reduced thyroxine levels in circulation. Remarkably, elimination of all three C2GnTs was permissive of viability and fertility. Core 2 O-glycan structures were reduced among tissues from individual C2GnT deficiencies and completely absent from triply deficient mice. C2GnT deficiency also induced alterations in I-branching, core 1 O-glycan formation, and O mannosylation. Although the absence of C2GnT and C4GnT activities is tolerable in vivo, core 2 O glycosylation exerts a significant influence on O-glycan biosynthesis and is important in multiple physiological processes. PMID:19349303

Citrus can help prevent vitamin A deficiency in developing countries

USDA-ARS?s Scientific Manuscript database

California is a major producer of tangerines and oranges, which contain carotenoids that form vitamin A. Deficiencies of this vitamin are common in southern Asia and Africa, causing blindness and more than one-half million deaths each year. We evaluated the potential of tangerines and oranges to pre...
Identifying Model-Based Reconfiguration Goals through Functional Deficiencies

NASA Technical Reports Server (NTRS)

Benazera, Emmanuel; Trave-Massuyes, Louise

2004-01-01

Model-based diagnosis is now advanced to the point autonomous systems face some uncertain and faulty situations with success. The next step toward more autonomy is to have the system recovering itself after faults occur, a process known as model-based reconfiguration. After faults occur, given a prediction of the nominal behavior of the system and the result of the diagnosis operation, this paper details how to automatically determine the functional deficiencies of the system. These deficiencies are characterized in the case of uncertain state estimates. A methodology is then presented to determine the reconfiguration goals based on the deficiencies. Finally, a recovery process interleaves planning and model predictive control to restore the functionalities in prioritized order.
Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.

PubMed Central

Stöckler, S.; Isbrandt, D.; Hanefeld, F.; Schmidt, B.; von Figura, K.

1996-01-01

In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine. Images Figure 2 PMID:8651275
Avascular Necrosis in the Contralateral Hip in Patients With Congenital Femoral Deficiency: A Report of 3 Cases.

PubMed

Brown, Timothy S; Wimberly, Robert L; Birch, John G

2017-01-01

Congenital femoral deficiency is an uncommon clinical entity. We report 3 patients who developed avascular necrosis of the hip in the long (normal) leg during longitudinal observation and/or treatment of congenital femoral deficiency. Patients were identified in limb length discrepancy clinic and their charts were retrospectively reviewed for clinical and radiographic data collection. We describe the occurrence of idiopathic avascular necrosis in the normal limb in patients being followed for limb length discrepancy. Although no conclusion could be drawn about the etiology of the avascular necrosis, we describe a previously undocumented relationship between congenital femoral deficiency and avascular necrosis in the contralateral hip. This occurred in our congenital femoral deficiency population at a rate higher than expected compared with published incidences of avascular necrosis of the hip in children. Level IV-case series.
Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution.

PubMed

Boueiz, Adel; Lutz, Sharon M; Cho, Michael H; Hersh, Craig P; Bowler, Russell P; Washko, George R; Halper-Stromberg, Eitan; Bakke, Per; Gulsvik, Amund; Laird, Nan M; Beaty, Terri H; Coxson, Harvey O; Crapo, James D; Silverman, Edwin K; Castaldi, Peter J; DeMeo, Dawn L

2017-03-15

Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers. A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
Nurse staffing and deficiencies in the largest for-profit nursing home chains and chains owned by private equity companies.

PubMed

Harrington, Charlene; Olney, Brian; Carrillo, Helen; Kang, Taewoon

2012-02-01

To compare staffing levels and deficiencies of the 10 largest U.S. for-profit nursing home chains with five other ownership groups and chain staffing and deficiencies before and after purchase by four private equity (PE) companies. Facilities for the largest for-profit chains were identified through Internet searches and company reports and matched with federal secondary data for 2003-2008 for each ownership group. Descriptive statistics and generalized estimation equation panel regression models examined staffing and deficiencies by ownership groups in the 2003-2008 period, controlling for facility characteristics, resident acuity, and market factors with state fixed effects. The top 10 for-profit chains had lower registered nurse and total nurse staffing hours than government facilities, controlling for other factors. The top 10 chains received 36 percent higher deficiencies and 41 percent higher serious deficiencies than government facilities. Other for-profit facilities also had lower staffing and higher deficiencies than government facilities. The chains purchased by PE companies showed little change in staffing levels, but the number of deficiencies and serious deficiencies increased in some postpurchase years compared with the prepurchase period. There is a need for greater study of large for-profit chains as well as those chains purchased by PE companies. © Health Research and Educational Trust.
StMYB44 negatively regulates phosphate transport by suppressing expression of PHOSPHATE1 in potato

USDA-ARS?s Scientific Manuscript database

Phosphorus is an important macronutrient for plant growth, but often deficient in soil. To understand the molecular basis of the complex responses of potato (Solanum tuberosum L.) to phosphate (Pi) deficiency stress, the RNA-Seq approach was taken to identify genes responding to Pi starvation in pot...
Fast neutron radiation induced Glu-B1 deficient lines of an elite bread wheat variety

USDA-ARS?s Scientific Manuscript database

Five isogenic wheat lines deficient in high-molecular weight subunit (HMW-GS) proteins encoded by the B-genome were identified from a fast-neutron radiation-mutagenized population of Summit, an elite variety of bread wheat (Triticum aestivum L.). The mutant lines differ from the wild-type progenit...
Educational Interventions for Visual-Motor Deficiencies That Affect Handwriting in School-Aged Children.

ERIC Educational Resources Information Center

Dikowski, Timothy J.

This practicum was designed to remediate handwriting skills in school-aged children who displayed visual-motor deficiencies that affect mechanical skills. Practicum goals were to: (1) identify and diagnose children with handwriting delays; (2) involve school and parent interaction by involving them with pre- and post-program assessment; (3)…
Anemia, micronutrient deficiencies, and malaria in children and women in Sierra Leone prior to the Ebola outbreak

USDA-ARS?s Scientific Manuscript database

To identify the factors associated with anemia and to document the severity of micronutrient deficiencies, malaria and inflammation, a nationally representative cross-sectional survey was conducted. A three-stage sampling procedure was used to randomly select children <5 years of age and adult women...
Genome-wide association analysis identifies candidate genes associated with iron deficiency chlorosis in soybean

USDA-ARS?s Scientific Manuscript database

Iron deficiency chlorosis (IDC) is a significant yield-limiting problem in some of the major soybean production regions in the United States. Soybean plants display a variety of symptoms, ranging from slight yellowing of the leaves to interveinal chlorosis and sometimes it is followed by stunted gr...
Assessing Students for Morality Education: A New Role for School Counselors

ERIC Educational Resources Information Center

Rayburn, Carole

2004-01-01

Misbehavior is related to moral deficiency in individuals or in systems. When moral deficiencies such as bullying and violence are identified, corrective measures can be taken. Religiousness and spirituality are related to the moral development of college students (Parks, 1993; Serow & Dreyden, 1990). Educational institutions need to take a more…
Vitamin D deficiency is prevalent in girls and women with rett syndrome

USDA-ARS?s Scientific Manuscript database

The aim of the study was to determine the prevalence of vitamin D deficiency and identify the relation between 25-hydroxyvitamin D (25-(OH)D) levels and the consumption of dietary sources of vitamin D or exposure to anticonvulsants in girls and women with Rett syndrome (RTT). Retrospective review of...
Deficient aversive-potentiated startle and the triarchic model of psychopathy: The role of boldness.

PubMed

Esteller, Àngels; Poy, Rosario; Moltó, Javier

2016-05-01

This study examined the contribution of the phenotypic domains of boldness, meanness, and disinhibition of the triarchic conceptualization of psychopathy (Patrick, Fowles, & Krueger, 2009) to deficient aversive-potentiated startle in a mixed-gender sample of 180 undergraduates. Eyeblink responses to noise probes were recorded during a passive picture-viewing task (erotica, neutral, threat, and mutilation). Deficient threat vs. neutral potentiation was uniquely related to increased boldness scores, thus suggesting that the diminished defensive reaction to aversive stimulation is specifically linked to the charm, social potency and venturesomeness features of psychopathy (boldness), but not to features such as callousness, coldheartedness and cruelty traits (meanness), even though both phenotypes theoretically share the same underlying low-fear disposition. Our findings provide further evidence of the differential association between distinct psychopathy components and deficits in defensive reactivity and strongly support the validity of the triarchic model of psychopathy in disentangling the etiology of this personality disorder. Copyright © 2016 Elsevier B.V. All rights reserved.
Early-Onset Autoimmune Disease as a Manifestation of Primary Immunodeficiency

PubMed Central

Carneiro-Sampaio, Magda; Coutinho, Antonio

2015-01-01

Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi–Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID. PMID:25999944
Novel recessive mutations in COQ4 cause severe infantile cardiomyopathy and encephalopathy associated with CoQ10 deficiency.

PubMed

Sondheimer, Neal; Hewson, Stacy; Cameron, Jessie M; Somers, Gino R; Broadbent, Jane Dunning; Ziosi, Marcello; Quinzii, Catarina Maria; Naini, Ali B

2017-09-01

Coenzyme Q 10 (CoQ 10 ) or ubiquinone is one of the two electron carriers in the mitochondrial respiratory chain which has an essential role in the process of oxidative phosphorylation. Defects in CoQ 10 synthesis are usually associated with the impaired function of CoQ 10 -dependent complexes I, II and III. The recessively transmitted CoQ 10 deficiency has been associated with a number of phenotypically and genetically heterogeneous groups of disorders manifesting at variable age of onset. The infantile, multisystemic presentation is usually caused by mutations in genes directly involved in CoQ 10 biosynthesis. To date, mutations in COQ1 ( PDSS1 and PDSS2 ), COQ2 , COQ4 , COQ6 , COQ7 , COQ8A / ADCK3 , COQ8B/ADCK4 , and COQ9 genes have been identified in patients with primary form of CoQ 10 deficiency. Here we report novel mutations in the COQ4 gene, which were identified in an infant with profound mitochondrial disease presenting with perinatal seizures, hypertrophic cardiomyopathy and severe muscle CoQ 10 deficiency.
Correcting Systemic Deficiencies in Our Scientific Infrastructure

PubMed Central

Doss, Mohan

2014-01-01

Scientific method is inherently self-correcting. When different hypotheses are proposed, their study would result in the rejection of the invalid ones. If the study of a competing hypothesis is prevented because of the faith in an unverified one, scientific progress is stalled. This has happened in the study of low dose radiation. Though radiation hormesis was hypothesized to reduce cancers in 1980, it could not be studied in humans because of the faith in the unverified linear no-threshold model hypothesis, likely resulting in over 15 million preventable cancer deaths worldwide during the past two decades, since evidence has accumulated supporting the validity of the phenomenon of radiation hormesis. Since our society has been guided by scientific advisory committees that ostensibly follow the scientific method, the long duration of such large casualties is indicative of systemic deficiencies in the infrastructure that has evolved in our society for the application of science. Some of these deficiencies have been identified in a few elements of the scientific infrastructure, and remedial steps suggested. Identifying and correcting such deficiencies may prevent similar tolls in the future. PMID:24910580
Neonatal screening for biotinidase deficiency: A 30-year single center experience.

PubMed

Porta, Francesco; Pagliardini, Veronica; Celestino, Isabella; Pavanello, Enza; Pagliardini, Severo; Guardamagna, Ornella; Ponzone, Alberto; Spada, Marco

2017-12-01

We reviewed the outcome of newborn screening for biotinidase deficiency performed at our department since 1987. Among 1,097,894 newborns screened, 461 were recalled, and 18 were identified as affected by complete or partial biotinidase deficiency (incidence 1:61,000, false positive rate 0.04%). The common missense mutation Q456H was found in 80% of patients with profound biotinidase deficiency. Of them, one patient harbored the novel mutation M399I in compound heterozygosity (M399I/Q456H). The complex allele A171T/D444H in cis was found in two patients with profound biotinidase deficiency (in homozygosity and in compound heterozygosity with the R211H mutation, respectively) and in one patient with partial biotinidase deficiency (in compound heterozygosity with the protective allele D444H in trans ). All detected patients were treated and followed up at our Center until present. Biotin therapy (10-20 mg/day) allowed the full prevention of clinical symptoms in all patients with no adverse effects. These excellent outcomes confirm that newborn screening for biotinidase deficiency is a very effective secondary prevention program.
BRUTUS and its paralogs, BTS LIKE1 and BTS LIKE2, encode important negative regulators of the iron deficiency response in Arabidopsis thaliana.

PubMed

Hindt, Maria N; Akmakjian, Garo Z; Pivarski, Kara L; Punshon, Tracy; Baxter, Ivan; Salt, David E; Guerinot, Mary Lou

2017-07-19

Iron (Fe) is required for plant health, but it can also be toxic when present in excess. Therefore, Fe levels must be tightly controlled. The Arabidopsis thaliana E3 ligase BRUTUS (BTS) is involved in the negative regulation of the Fe deficiency response and we show here that the two A. thaliana BTS paralogs, BTS LIKE1 (BTSL1) and BTS LIKE2 (BTSL2) encode proteins that act redundantly as negative regulators of the Fe deficiency response. Loss of both of these E3 ligases enhances tolerance to Fe deficiency. We further generated a triple mutant with loss of both BTS paralogs and a partial loss of BTS expression that exhibits even greater tolerance to Fe-deficient conditions and increased Fe accumulation without any resulting Fe toxicity effects. Finally, we identified a mutant carrying a novel missense mutation of BTS that exhibits an Fe deficiency response in the root when grown under both Fe-deficient and Fe-sufficient conditions, leading to Fe toxicity when plants are grown under Fe-sufficient conditions.
Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort.

PubMed

Martín, Martín G; Lindberg, Iris; Solorzano-Vargas, R Sergio; Wang, Jiafang; Avitzur, Yaron; Bandsma, Robert; Sokollik, Christiane; Lawrence, Sarah; Pickett, Lindsay A; Chen, Zijun; Egritas, Odul; Dalgic, Buket; Albornoz, Valeria; de Ridder, Lissy; Hulst, Jessie; Gok, Faysal; Aydoğan, Ayşen; Al-Hussaini, Abdulrahman; Gok, Deniz Engin; Yourshaw, Michael; Wu, S Vincent; Cortina, Galen; Stanford, Sara; Georgia, Senta

2013-07-01

Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

PubMed

Munns, Craig F; Simm, Peter J; Rodda, Christine P; Garnett, Sarah P; Zacharin, Margaret R; Ward, Leanne M; Geddes, Janet; Cherian, Sarah; Zurynski, Yvonne; Cowell, Christopher T

2012-04-16

To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. Australian paediatricians and child health workers, January 2006 - July 2007. Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.
Reduced risk for placental malaria in iron deficient women

PubMed Central

2011-01-01

Background Nutritional iron deficiency may limit iron availability to the malaria parasite reducing infection risk, and/or impair host immunity thereby increasing this risk. In pregnant women, there is evidence of an adverse effect with iron supplementation, but the few reported studies are strongly confounded. Methods A case control study in pregnant Malawian women was undertaken in Chikhwawa southern Malawi in order to describe iron status in relation to placental malaria controlling for several confounding factors. Pregnancy characteristics were obtained and a blood sample at delivery. A full blood count was performed and serum ferritin and transferrin receptor quantified by enzyme-linked immunoassay. DNA analysis was used to identify genetic polymorphisms for ABO phenotype, hemoglobin HbS, and glucose -6 phosphate dehydrogenase deficiency. Placental tissue was obtained and malaria histology classified as active, past or no malaria infection. Results 112 cases with placental malaria were identified and 110 women with no evidence of placental infection. Iron deficiency was less frequent in women with placental Plasmodium falciparum infection. In those with acute, chronic or past placental infections the odds ratio for iron deficiency was 0.4, 95% CI 0.2-0.8, p = 0.01; for acute and chronic infections 0.4, 0.2-0.8, p = 0.006; for acute infection 0.3, 0.1-0.7, p = 0.001. The association was greater in multigravidae. Conclusion Women with either acute, or acute and chronic placental malaria were less likely to have iron deficiency than women without placental malaria infection There is a priority to establish if reversing iron deficiency through iron supplementation programs either prior to or during pregnancy enhances malaria risk. PMID:21345193
Identification of Mediterranean mutation in Egyptian favism patients.

PubMed

Osman, H G; Zahran, F M; El-Sokkary, A M A; El-Said, A; Sabry, A M

2014-10-01

Identify and screen the G6PD Mediterranean mutation in favism patients by applying a Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR). A total of 114 unrelated Egyptians patients were included in the present study; their ages ranged between (2-9) years with male to female ratio 4.5:1. G6PD activity was determined qualitatively from red cell hemolysate during attack. The G6PD Mediterranean mutation in patients has been identified by ARMS-PCR. G6PD deficiency was detected in 87.7%, (n=100). The frequency of G6PD Mediterranean mutation was (94.7%), (n=108). The association between G6PD deficiency and Mediterranean mutation was a highly significant. Glucose-6-phosphate dehydrogenase Mediterranean mutation is one of the most common mutations causing G6PD deficiency among Egyptian children with favism.
Ultraviolet Observations of Three Dwarf Cepheids

NASA Astrophysics Data System (ADS)

Sturch, Conrad R.

Ultraviolet observations of three dwarf Cepheids (VZ Cnc, SX Phe, and AI Vel) have been obtained with the ANS. Analysis of these observations (Sturch and WU 1982) reveals that the flux distributions observed for each of these objects exhibit UV deficiencies which increase monotonically with decreasing wavelengths. The largest UV deficiencies are noted for SX Phe which has been identified with group of dwarf Cepheids with low metallicity and low luminosity, two attributes that are expected to have opposite effects on the UV flux distribution. It is proposed to obtain low dispersion IUE spectra of the three stars throughout each of their light cycles. Such observations will identify spectral features responsible for the flux deficiencies and will provide data necessary for a detailed comparison with model atmospheres. Knowledge of atmospheric parameters will lead to a better understanding of the evolutionary status of dwarf Cepheids.
25-hydroxy vitamin D deficiency following pediatric hematopoietic stem cell transplant.

PubMed

Duncan, Christine N; Vrooman, Lynda; Apfelbaum, Erin M; Whitley, Katherine; Bechard, Lori; Lehmann, Leslie E

2011-05-01

Children may be at increased risk for vitamin D deficiency following HSCT because of lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, malabsorption, and the use of certain medications. We prospectively assessed the prevalence of and risk factors for 25-hydroxy (25-OH) vitamin D deficiency in 67 patients transplanted at our institution. 25-OH vitamin D levels were checked during 3 separate 4-week periods in the spring, autumn, and winter. Subjects were <2 years following transplant and/or being treated for chronic graft-versus-host disease (cGVHD). Levels less than 20 ng/mL were considered deficient, and those less than 30 ng/mL were considered insufficient. The mean 25-OH vitamin D level was 22.8 ng/mL (range: 7-46.2). A total of 80.6% (confidence interval [CI] 69.1%-89.3%) of patients had a level less than the lower limit of the institutional normal range. The deficiency rate was 37.3% (CI 25.8%-50%). The mean parathyroid hormone (PTH) level was 77.5 (SD = 80.5). There was no correlation between 25-OH vitamin D and PTH levels. We evaluated potential risk factors for 25-OH vitamin D deficiency including age, season of testing, sun exposure, sunscreen use, use of steroid or calcineurin inhibitor, race, and dairy intake. In multivariate logistic regression, only older age was found to be a risk factor for deficiency (P = .004). Patients with deficient levels were treated with 50,000 IU of ergocalciferol once weekly for 6 weeks. A postrepletion 25-OH level was available for 22 patients. The majority of repleted patients had a normal posttreatment level (63.6%). The postsupplementation level corrected into the insufficient range for 31.8% of patients and 4.6% remained deficient. Vitamin D insufficiency and deficiency are common following HSCT. Further investigation into potential risk factors and the appropriate supplementation for these patients is warranted. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Prevalence, genetic variants and clinical implications of G-6-PD deficiency in Burkina Faso: a systematic review.

PubMed

Ouattara, Abdoul Karim; Yameogo, Pouiré; Traore, Lassina; Diarra, Birama; Assih, Maléki; Compaore, Tegwindé Rébéca; Obiri-Yeboah, Dorcas; Soubeiga, Serge Théophile; Djigma, Florencia Wendkuuni; Simpore, Jacques

2017-11-23

It is now well-known that some antimalarials such as primaquine may induce severe hemolytic anemia in people with G-6-PD deficiency. Antimalarial drug prescriptions must, therefore take into account the patient's G-6-PD status in malaria endemic areas such as Burkina Faso, where the prevalence of this genetic abnormality is relatively high. Although great clinical heterogeneity is observed depending on the molecular nature of the deficiency and the residual enzyme activity in the red blood cell, there is very poor data on the prevalence of G-6-PD deficiency and the distribution of involved genetic variants in Burkina Faso. In this systematic review, we present a synthesis of the various studies carried out on the G-6-PD deficiency in Burkina Faso in order to determine its prevalence, probable distribution of the genetic variants involved and their clinical implications for a national systematic screening policy among the groups most vulnerable to malaria. A systematic review was carried out to analyze available published data on the prevalence, phenotypes and mutations responsible for G-6-PD deficiency in Burkina Faso. The key words used were "G-6-PD deficiency AND Burkina Faso" or "Déficit en G-6-PD AND Burkina Faso" in French. To identify the relevant articles, two independent reviewers reviewed the titles, abstracts and the full text of the selected papers. An average prevalence of 16.6% (183/1100; CI 95%: 0.145-0.190) and 6.5% (69/1066; CI 95%: 0.051-0.081) of G-6-PD deficiency was found respectively in men and women in this systematic review. Although the predominance (99.8% of G-6-PD deficient cases) of 202A/376G G-6-PD A- variant, the Santamaria and Betica Selma variants were identified in Burkina Faso. Independently of the method used, the enzymatic deficiency was significantly higher in males (2.5-20.5%) compared to females (3.3-12.3%). This systematic review suggests that despite the ubiquity of the 202A/376G G-6-PD A- variant in Burkina Faso, it will be necessary to consider the Santamaria and Betica Selma variants although their frequencies remain to be specified. A systematic screening of the G-6-PD deficiency is also needed to prevent the occurrence of iatrogenic hemolytic accidents.
Plasmodium falciparum clearance with artemisinin-based combination therapy (ACT) in patients with glucose-6-phosphate dehydrogenase deficiency in Mali.

PubMed

Kone, Abdoulaye K; Sagara, Issaka; Thera, Mahamadou A; Dicko, Alassane; Guindo, Aldiouma; Diakite, Seidina; Kurantsin-Mills, Joseph; Djimde, Abdoulaye; Walcourt, Asikiya; Doumbo, Ogabara

2010-11-21

Artemisinin-based combination therapy (ACT) is currently the most effective medicine for the treatment of uncomplicated malaria. Artemisinin has previously been shown to increase the clearance of Plasmodium falciparum in malaria patients with haemoglobin E trait, but it did not increase parasite inhibition in an in vitro study using haemoglobin AS erythrocytes. The current study describes the efficacy of artemisinin derivatives on P. falciparum clearance in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), a haemoglobin enzyme deficiency, not yet studied in the same context, but nonetheless is a common in malaria endemic areas, associated with host protection against uncomplicated and severe malaria. The impact of G6PD deficiency on parasite clearance with ACT treatment was compared between G6PD-deficient patients and G6PD-normal group. Blood samples from children and adults participants (1 to 70 years old) with uncomplicated P. falciparum malaria residing in Kambila, Mali were analysed. Study participants were randomly assigned to receive either artemether-lumefantrine (Coartem®) or artesunate plus mefloquine (Artequin™). A restriction-fragment length polymorphism analysis of PCR-amplified DNA samples was used to identify the (A-) allele of the gene mutation responsible for G6PD deficiency (G6PD*A-). 470 blood samples were thus analysed and of these, DNA was extracted from 315 samples using the QIAamp kit for PCR to identify the G6PD*A- gene. The DNA amplified from 315 samples using PCR showed that G6PD*A- deficiency was present in 56 participants (17.8%). The distribution of the specific deficiency was 1%, 7% and, 9.8% respectively for homozygous, hemizygous, and heterozygous genotypes. Before treatment, the median parasitaemia and other baseline characteristics (mean haemoglobin, sex and age groups) between G6PD deficiency (hemizygous, heterozygous, and homozygous) and G6PD-normal participants were comparable (p > 0.05). After treatment, parasite clearance did not change significantly whether the participants were G6PD deficient or G6PD normal on day 1 (OR = 1.3; CI = 0.70-2.47; p > 0.05) and on day 2 (OR = 0.859; CI = 0.097-7.61; p > 0.05). The presence of G6PD deficiency does not appear to significantly influence the clearance of P. falciparum in the treatment of uncomplicated malaria using ACT.
Kangaroo – A pattern-matching program for biological sequences

PubMed Central

2002-01-01

Background Biologists are often interested in performing a simple database search to identify proteins or genes that contain a well-defined sequence pattern. Many databases do not provide straightforward or readily available query tools to perform simple searches, such as identifying transcription binding sites, protein motifs, or repetitive DNA sequences. However, in many cases simple pattern-matching searches can reveal a wealth of information. We present in this paper a regular expression pattern-matching tool that was used to identify short repetitive DNA sequences in human coding regions for the purpose of identifying potential mutation sites in mismatch repair deficient cells. Results Kangaroo is a web-based regular expression pattern-matching program that can search for patterns in DNA, protein, or coding region sequences in ten different organisms. The program is implemented to facilitate a wide range of queries with no restriction on the length or complexity of the query expression. The program is accessible on the web at http://bioinfo.mshri.on.ca/kangaroo/ and the source code is freely distributed at http://sourceforge.net/projects/slritools/. Conclusion A low-level simple pattern-matching application can prove to be a useful tool in many research settings. For example, Kangaroo was used to identify potential genetic targets in a human colorectal cancer variant that is characterized by a high frequency of mutations in coding regions containing mononucleotide repeats. PMID:12150718
Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice

PubMed Central

Yang, Hao; Wang, Shu Pei; Mitchell, Grant A.

2017-01-01

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. PMID:29232702
Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

PubMed

Xia, Bo; Cai, Guo He; Yang, Hao; Wang, Shu Pei; Mitchell, Grant A; Wu, Jiang Wei

2017-12-01

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.
A meta-analysis of pica and micronutrient status.

PubMed

Miao, Diana; Young, Sera L; Golden, Christopher D

2015-01-01

Pica is the craving for and consumption of nonfood items, including the ingestion of earth (geophagy), raw starch (amylophagy), and ice (pagophagy). Pica has long been associated with micronutrient deficiencies, but the strength of this relationship is unclear. We aimed to evaluate the association between pica behavior and the risk of being anemic or having low hemoglobin (Hb), hematocrit (Hct), or plasma zinc (Zn) concentrations. We systematically reviewed studies in which micronutrient levels were reported by pica status. We calculated the pooled odds ratio for anemia or weighted mean difference in Hb, Hct, or Zn concentrations between groups practicing or not practicing pica behaviors. Forty-three studies including 6,407 individuals with pica behaviors and 10,277 controls were identified. Pica was associated with 2.35 times greater odds of anemia (95% CI: 1.94-2.85, P < 0.001), lower Hb concentration (-0.65 g/dl, 95% CI: -0.83 to -0.48 g/dl, P < 0.001), lower Hct concentration (-1.15%, 95% CI: -1.61 to -0.70%, P < 0.001), and lower Zn concentration (-34.3 μg/dl, 95% CI: -59.58 to -9.02 μg/dl, P = 0.008). Statistical significance persisted after excluding outliers and in subgroup analyses by pica type and life stage. Pica is significantly associated with increased risk for anemia and low Hb, Hct, and plasma Zn. Although the direction of the causal relationship between pica and micronutrient deficiency is unknown, the magnitude of these relationships is comparable to other well-recognized causes of micronutrient deficiencies. Pica warrants greater public health attention; specifically the potential physiological mechanisms underpinning the relationship between pica and micronutrient deficiencies merit further study. © 2014 Wiley Periodicals, Inc.
A meta-analysis of pica and micronutrient status

PubMed Central

Miao, Diana; Young, Sera L; Golden, Christopher D

2014-01-01

Objectives Pica is the craving for and consumption of non-food items, including the ingestion of earth (geophagy), raw starch (amylophagy), and ice (pagophagy). Pica has long been associated with micronutrient deficiencies, but the strength of this relationship is unclear. We aimed to evaluate the association between pica behavior and the risk of being anemic or having low hemoglobin (Hb), hematocrit (Hct), or plasma zinc (Zn) concentrations. Methods We systematically reviewed studies in which micronutrient levels were reported by pica status. We calculated the pooled odds ratio for anemia or weighted mean difference in Hb, Hct, or Zn concentrations between groups practicing or not practicing pica behaviors. Results Forty-three studies including 6407 individuals with pica behaviors and 10,277 controls were identified. Pica was associated with 2.4 times greater odds of anemia (95% CI: 1.94–2.85, p<0.001), lower Hb concentration (−0.65 g/dL, 95% CI: −0.83–−0.48 g/dL, p<0.001), lower Hct concentration (−1.15%, 95% CI: −1.61–−0.70%, p<0.001), and lower Zn concentration (−34.3 μg/dL, 95% CI: −59.58–−9.02 μg/dL, p=0.008). Statistical significance persisted after excluding outliers and in subgroup analyses by pica type and life stage. Conclusions Pica is significantly associated with increased risk for anemia and low Hb, Hct, and plasma Zn. Although the direction of the causal relationship between pica and micronutrient deficiency is unknown, the magnitude of these relationships is comparable to other well-recognized causes of micronutrient deficiencies. Pica warrants greater public health attention; specifically a potential physiological mechanism causing the relationship between pica and micronutrient deficiencies merits further study. PMID:25156147
BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21

PubMed Central

Lee, Hyemin; Dai, Fangyan; Zhuang, Li; Xiao, Zhen-Dong; Kim, Jongchan; Zhang, Yilei; Ma, Li; You, M. James; Wang, Zhong; Gan, Boyi

2016-01-01

BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology. PMID:26992241
Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among malaria patients in Upper Myanmar.

PubMed

Lee, Jinyoung; Kim, Tae Im; Kang, Jung-Mi; Jun, Hojong; Lê, Hương Giang; Thái, Thị Lam; Sohn, Woon-Mok; Myint, Moe Kyaw; Lin, Khin; Kim, Tong-Soo; Na, Byoung-Kuk

2018-03-16

Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) deficiency is one of the most common X-linked recessive hereditary disorders in the world. Primaquine (PQ) has been used for radical cure of P. vivax to prevent relapse. Recently, it is also used to reduce P. falciparum gametocyte carriage to block transmission. However, PQ metabolites oxidize hemoglobin and generate excessive reactive oxygen species which can trigger acute hemolytic anemia in malaria patients with inherited G6PD deficiency. A total of 252 blood samples collected from malaria patients in Myanmar were used in this study. G6PD variant was analysed by a multiplex allele specific PCR kit, DiaPlexC™ G6PD Genotyping Kit [Asian type]. The accuracy of the multiplex allele specific PCR was confirmed by sequencing analysis. Prevalence and distribution of G6PD variants in 252 malaria patients in Myanmar were analysed. Six different types of G6PD allelic variants were identified in 50 (7 females and 43 males) malaria patients. The predominant variant was Mahidol (68%, 34/50), of which 91.2% (31/34) and 8.8% (3/34) were males and females, respectively. Other G6PD variants including Kaiping (18%, 9/50), Viangchan (6%, 3/50), Mediterranean (4%, 2/50), Union (2%, 1/50) and Canton (2%, 1/50) were also observed. Results of this study suggest that more concern for proper and safe use of PQ as a radical cure of malaria in Myanmar is needed by combining G6PD deficiency test before PQ prescription. Establishment of a follow-up system to monitor potential PQ toxicity in malaria patients who are given PQ is also required.
Prevalence and genetic variants of G6PD deficiency among two Malagasy populations living in Plasmodium vivax-endemic areas.

PubMed

Howes, Rosalind E; Chan, Ernest R; Rakotomanga, Tovonahary Angelo; Schulte, Seth; Gibson, John; Zikursh, Melinda; Franchard, Thierry; Ramiranirina, Brune; Ratsimbasoa, Arsène; Zimmerman, Peter A

2017-04-04

The prevalence and variants of G6PD deficiency in the Plasmodium vivax-endemic zones of Madagascar remain unknown. The admixed African-Austronesian origins of the Malagasy population make it probable that a heterogeneous mix of genetic variants with a spectrum of clinical severity will be circulating. This would have implications for the widespread use of P. vivax radical cure therapy. Two study populations in the P. vivax-endemic western foothills region of Madagascar were selected for G6PD screening. Both the qualitative fluorescent spot test and G6PD genotyping were used to screen all participants. A total of 365 unrelated male volunteers from the Tsiroanomandidy, Mandoto, and Miandrivazo districts of Madagascar were screened and 12.9% were found to be phenotypically G6PD deficient. Full gene sequencing of 95 samples identified 16 single nucleotide polymorphisms, which were integrated into a genotyping assay. Genotyping (n = 291) found one individual diagnosed with the severe G6PD Mediterranean C563T mutation, while the remaining G6PD deficient samples had mutations of African origin, G6PD A- and G6PD A. Deployment of P. vivax radical cure in Madagascar must be considerate of the risks presented by the observed prevalence of G6PDd prevalence. The potential morbidity associated with cumulative episodes of P. vivax clinical relapses requires a strategy for increasing access to safe radical cure. The observed dominance of African G6PDd haplotypes is surprising given the known mixed African-Austronesian origins of the Malagasy population; more widespread surveying of G6PDd epidemiology across the island would be required to characterize the distribution of G6PD haplotypes across Madagascar.
Deficient expression of aldehyde dehydrogenase 1A1 is consistent with increased sensitivity of Gorlin syndrome patients to radiation carcinogenesis.

PubMed

Wright, Aaron T; Magnaldo, Thierry; Sontag, Ryan L; Anderson, Lindsey N; Sadler, Natalie C; Piehowski, Paul D; Gache, Yannick; Weber, Thomas J

2015-06-01

Human phenotypes that are highly susceptible to radiation carcinogenesis have been identified. Sensitive phenotypes often display robust regulation of molecular features that modify biological response, which can facilitate identification of the pathways/networks that contribute to pathophysiological outcomes. Here we interrogate primary dermal fibroblasts isolated from Gorlin syndrome patients (GDFs), who display a pronounced inducible tumorigenic response to radiation, in comparison to normal human dermal fibroblasts (NHDFs). Our approach exploits newly developed thiol reactive probes to define changes in protein thiol profiles in live cell studies, which minimizes artifacts associated with cell lysis. Redox probes revealed deficient expression of an apparent 55 kDa protein thiol in GDFs from independent Gorlin syndrome patients, compared with NHDFs. Proteomics tentatively identified this protein as aldehyde dehydrogenase 1A1 (ALDH1A1), a key enzyme regulating retinoic acid synthesis, and ALDH1A1 protein deficiency in GDFs was confirmed by Western blot. A number of additional protein thiol differences in GDFs were identified, including radiation responsive annexin family members and lamin A/C. Collectively, candidates identified in our study have plausible implications for radiation health effects and cancer susceptibility. © 2013 Wiley Periodicals, Inc.
Long-term boron-deficiency-responsive genes revealed by cDNA-AFLP differ between Citrus sinensis roots and leaves

PubMed Central

Lu, Yi-Bin; Qi, Yi-Ping; Yang, Lin-Tong; Lee, Jinwook; Guo, Peng; Ye, Xin; Jia, Meng-Yang; Li, Mei-Li; Chen, Li-Song

2015-01-01

Seedlings of Citrus sinensis (L.) Osbeck were supplied with boron (B)-deficient (without H3BO3) or -sufficient (10 μM H3BO3) nutrient solution for 15 weeks. We identified 54 (38) and 38 (45) up (down)-regulated cDNA-AFLP bands (transcript-derived fragments, TDFs) from B-deficient leaves and roots, respectively. These TDFs were mainly involved in protein and amino acid metabolism, carbohydrate and energy metabolism, nucleic acid metabolism, cell transport, signal transduction, and stress response and defense. The majority of the differentially expressed TDFs were isolated only from B-deficient roots or leaves, only seven TDFs with the same GenBank ID were isolated from the both. In addition, ATP biosynthesis-related TDFs were induced in B-deficient roots, but unaffected in B-deficient leaves. Most of the differentially expressed TDFs associated with signal transduction and stress defense were down-regulated in roots, but up-regulated in leaves. TDFs related to protein ubiquitination and proteolysis were induced in B-deficient leaves except for one TDF, while only two down-regulated TDFs associated with ubiquitination were detected in B-deficient roots. Thus, many differences existed in long-term B-deficiency-responsive genes between roots and leaves. In conclusion, our findings provided a global picture of the differential responses occurring in B-deficient roots and leaves and revealed new insight into the different adaptive mechanisms of C. sinensis roots and leaves to B-deficiency at the transcriptional level. PMID:26284101
Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency

PubMed Central

Grabrucker, Stefanie; Boeckers, Tobias M.; Grabrucker, Andreas M.

2016-01-01

Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior. PMID:26973485
Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms

PubMed Central

2012-01-01

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability. PMID:23234264
Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

PubMed

Cheillan, David; Joncquel-Chevalier Curt, Marie; Briand, Gilbert; Salomons, Gajja S; Mention-Mulliez, Karine; Dobbelaere, Dries; Cuisset, Jean-Marie; Lion-François, Laurence; Portes, Vincent Des; Chabli, Allel; Valayannopoulos, Vassili; Benoist, Jean-François; Pinard, Jean-Marc; Simard, Gilles; Douay, Olivier; Deiva, Kumaran; Afenjar, Alexandra; Héron, Delphine; Rivier, François; Chabrol, Brigitte; Prieur, Fabienne; Cartault, François; Pitelet, Gaëlle; Goldenberg, Alice; Bekri, Soumeya; Gerard, Marion; Delorme, Richard; Tardieu, Marc; Porchet, Nicole; Vianey-Saban, Christine; Vamecq, Joseph

2012-12-13

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

Creatine Deficiency Syndrome could be Missed Easily: A Case Report of Guanidinoacetate Methyltransferase Deficiency Presented with Neurodevelopmental Delay, Seizures, and Behavioral Changes, but Normal Structural MRI.

PubMed

Pacheva, Iliyana; Ivanov, Ivan; Penkov, Marin; Kancheva, Daliya; Jordanova, Albena; Ivanova, Mariya

2016-09-01

A case with GAMT deficiency (homozygous c.64dupG mutation) presented with neurodevelopmental delay, rare seizures, behavioral disturbances, and mild hypotonia, posing diagnostic challenges. Metabolic investigations showed low creatinine in plasma and urine (guanidinoacetate couldn't be investigated) and slightly elevated lactate. MRI was normal. Correct diagnosis was possible only after MR spectroscopy was performed at age 5½ years. A homozygous c.64dupG mutation of the GAMT gene was identified in the proband. In conclusion, every case with neurodevelopmental delay or arrest, especially when accompanied by seizures, behavioral impairment, muscle hypotonia or extrapyramidal symptoms should undergo MRI with MR spectroscopy. Normal structural MRI doesn't exclude a creatine deficiency syndrome. Biochemical investigations of guanidinoacetate, creatine, and creatinine in body fluid should be done to diagnose cerebral creatine deficiency syndromes and to specify the deficient enzyme. Thus, a treatable disease will not be missed. © 2016 by the Association of Clinical Scientists, Inc.
Coenzyme Q10 deficiencies in neuromuscular diseases.

PubMed

Artuch, Rafael; Salviati, Leonardo; Jackson, Sandra; Hirano, Michio; Navas, Plácido

2009-01-01

Coenzyme Q (CoQ) is an essential component of the respiratory chain but also participates in other mitochondrial functions such as regulation of the transition pore and uncoupling proteins. Furthermore, this compound is a specific substrate for enzymes of the fatty acids beta-oxidation pathway and pyrimidine nucleotide biosynthesis. Furthermore, CoQ is an antioxidant that acts in all cellular membranes and lipoproteins. A complex of at least ten nuclear (COQ) genes encoded proteins synthesizes CoQ but its regulation is unknown. Since 1989, a growing number of patients with multisystemic mitochondrial disorders and neuromuscular disorders showing deficiencies of CoQ have been identified. CoQ deficiency caused by mutation(s) in any of the COQ genes is designated primary deficiency. Other patients have displayed other genetic defects independent on the CoQ biosynthesis pathway, and are considered to have secondary deficiencies. This review updates the clinical and molecular aspects of both types of CoQ deficiencies and proposes new approaches to understanding their molecular bases.
The impact of homologous recombination repair deficiency on depleted uranium clastogenicity in Chinese hamster ovary cells: XRCC3 protects cells from chromosome aberrations, but increases chromosome fragmentation.

PubMed

Holmes, Amie L; Joyce, Kellie; Xie, Hong; Falank, Carolyne; Hinz, John M; Wise, John Pierce

2014-04-01

Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive. DU is genotoxic, inducing DNA double strand breaks, chromosome damage and mutations, but the mechanisms of genotoxicity or repair pathways involved in protecting cells against DU-induced damage remain unknown. The purpose of this study was to investigate the effects of homologous recombination repair deficiency on DU-induced genotoxicity using RAD51D and XRCC3-deficient Chinese hamster ovary (CHO) cell lines. Cells deficient in XRCC3 (irs1SF) exhibited similar cytotoxicity after DU exposure compared to wild-type (AA8) and XRCC3-complemented (1SFwt8) cells, but DU induced more break-type and fusion-type lesions in XRCC3-deficient cells compared to wild-type and XRCC3-complemented cells. Surprisingly, loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. DU induced selective X-chromosome fragmentation irrespective of RAD51D status, but loss of XRCC3 nearly eliminated fragmentation observed after DU exposure in wild-type and XRCC3-complemented cells. Thus, XRCC3, but not RAD51D, protects cells from DU-induced breaks and fusions and also plays a role in DU-induced chromosome fragmentation. Copyright © 2014 Elsevier B.V. All rights reserved.
Preclinical Demonstration of Lentiviral Vector-mediated Correction of Immunological and Metabolic Abnormalities in Models of Adenosine Deaminase Deficiency

PubMed Central

Carbonaro, Denise A; Zhang, Lin; Jin, Xiangyang; Montiel-Equihua, Claudia; Geiger, Sabine; Carmo, Marlene; Cooper, Aaron; Fairbanks, Lynette; Kaufman, Michael L; Sebire, Neil J; Hollis, Roger P; Blundell, Michael P; Senadheera, Shantha; Fu, Pei-Yu; Sahaghian, Arineh; Chan, Rebecca Y; Wang, Xiaoyan; Cornetta, Kenneth; Thrasher, Adrian J; Kohn, Donald B; Gaspar, H Bobby

2014-01-01

Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)–deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV EFS ADA). In ADA−/− mice, LV EFS ADA displayed high-efficiency gene transfer and sufficient ADA expression to rescue ADA−/− mice from their lethal phenotype with good thymic and peripheral T- and B-cell reconstitution. Human ADA-deficient CD34+ cells transduced with 1–5 × 107 TU/ml had 1–3 vector copies/cell and expressed 1–2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV EFS ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV EFS ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, while reducing the potential for vector-mediated insertional mutagenesis. PMID:24256635
A Tale of Treatable Infantile Neuroregression and Diagnostic Dilemma with Glutaric Aciduria Type I

PubMed Central

Yoganathan, Sangeetha; Varman, Mugil; Oommen, Samuel Philip; Thomas, Maya

2017-01-01

Nutritional deficiencies related neurological manifestations are not uncommon in infants and children. Here, we describe an infant with Vitamin B12 deficiency due to depleted maternal Vitamin B12 status presenting with progressive encephalopathy and extrapyramidal signs. Diagnosis of infantile tremor syndrome was established in our patient based on the clinical and biochemical parameters. Magnetic resonance imaging had shown frontotemporal atrophy with widened Sylvian fissures and prominent cerebrospinal fluid spaces. Clinical and imaging findings might create a diagnostic dilemma with glutaric aciduria type I. Knowledge and identification of infantile tremor syndrome are essential, as it is a potentially treatable disorder. Our patient had significant developmental gains with Vitamin B12 treatment and infant stimulation program. Vitamin B12 deficiency must be looked for as a cause of neuroregression in children hailing from low socioeconomic status, infants of vegetarian mother, and infants with delayed or improper weaning. Screening for Vitamin B12 deficiency is essential in all infants and children with unexplained neuroregression, as this disorder is potentially treatable. More population-based studies in India are needed to explore the prevalence of Vitamin B12 deficiency in pregnant and lactating women and also to assess the need for Vitamin B12 supplementation during pregnancy and lactation. PMID:29675077
A Tale of Treatable Infantile Neuroregression and Diagnostic Dilemma with Glutaric Aciduria Type I.

PubMed

Yoganathan, Sangeetha; Varman, Mugil; Oommen, Samuel Philip; Thomas, Maya

2017-01-01

Nutritional deficiencies related neurological manifestations are not uncommon in infants and children. Here, we describe an infant with Vitamin B12 deficiency due to depleted maternal Vitamin B12 status presenting with progressive encephalopathy and extrapyramidal signs. Diagnosis of infantile tremor syndrome was established in our patient based on the clinical and biochemical parameters. Magnetic resonance imaging had shown frontotemporal atrophy with widened Sylvian fissures and prominent cerebrospinal fluid spaces. Clinical and imaging findings might create a diagnostic dilemma with glutaric aciduria type I. Knowledge and identification of infantile tremor syndrome are essential, as it is a potentially treatable disorder. Our patient had significant developmental gains with Vitamin B12 treatment and infant stimulation program. Vitamin B12 deficiency must be looked for as a cause of neuroregression in children hailing from low socioeconomic status, infants of vegetarian mother, and infants with delayed or improper weaning. Screening for Vitamin B12 deficiency is essential in all infants and children with unexplained neuroregression, as this disorder is potentially treatable. More population-based studies in India are needed to explore the prevalence of Vitamin B12 deficiency in pregnant and lactating women and also to assess the need for Vitamin B12 supplementation during pregnancy and lactation.
Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle

PubMed Central

Winter, Lilli; Staszewska, Ilona; Mihailovska, Eva; Fischer, Irmgard; Goldmann, Wolfgang H.; Schröder, Rolf; Wiche, Gerhard

2014-01-01

The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD. PMID:24487589
Pilot-scale cultivation of wall-deficient transgenic Chlamydomonas reinhardtii strains expressing recombinant proteins in the chloroplast.

PubMed

Zedler, Julie A Z; Gangl, Doris; Guerra, Tiago; Santos, Edgar; Verdelho, Vitor V; Robinson, Colin

2016-08-01

Microalgae have emerged as potentially powerful platforms for the production of recombinant proteins and high-value products. Chlamydomonas reinhardtii is a potentially important host species due to the range of genetic tools that have been developed for this unicellular green alga. Transformation of the chloroplast genome offers important advantages over nuclear transformation, and a wide range of recombinant proteins have now been expressed in the chloroplasts of C. reinhardtii strains. This is often done in cell wall-deficient mutants that are easier to transform. However, only a single study has reported growth data for C. reinhardtii grown at pilot scale, and the growth of cell wall-deficient strains has not been reported at all. Here, we report the first pilot-scale growth study for transgenic, cell wall-deficient C. reinhardtii strains. Strains expressing a cytochrome P450 (CYP79A1) or bifunctional diterpene synthase (cis-abienol synthase, TPS4) were grown for 7 days under mixotrophic conditions in a Tris-acetate-phosphate medium. The strains reached dry cell weights of 0.3 g/L within 3-4 days with stable expression levels of the recombinant proteins during the whole upscaling process. The strains proved to be generally robust, despite the cell wall-deficient phenotype, but grew poorly under phototrophic conditions. The data indicate that cell wall-deficient strains may be highly amenable for transformation and suitable for commercial-scale operations under mixotrophic growth regimes.
Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency.

PubMed

Shin, Ha Kyung; Grahame, George; McCandless, Shawn E; Kerr, Douglas S; Bedoyan, Jirair K

2017-11-01

Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder. We sought to evaluate the diagnostic sensitivity and variability of the various PDC enzyme assays in females and males at the Center for Inherited Disorders of Energy Metabolism (CIDEM). CIDEM data were filtered by lactic acidosis and functional PDC deficiency in at least one cell/tissue type (blood lymphocytes, cultured fibroblasts or skeletal muscle) identifying 186 subjects (51% male and 49% female), about half were genetically resolved with 78% of those determined to have a pathogenic PDHA1 mutation. Assaying PDC in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1, was highly sensitive irrespective of gender; 97% (95% confidence interval [CI]: 90%-100%) and 91% (95% CI: 82%-100%) in females and males, respectively. In contrast to the fibroblast-based testing, the lymphocyte- and muscle-based testing were not sensitive (36% [95% CI: 11%-61%, p=0.0003] and 58% [95% CI: 30%-86%, p=0.014], respectively) for identifying known PDC deficient females with pathogenic PDHA1 mutations. In males with a known PDHA1 mutation, the sensitivity of the various cell/tissue assays (75% lymphocyte, 91% fibroblast and 88% muscle) were not statistically different, and the discordance frequency due to the specific cell/tissue used for assaying PDC was 0.15±0.11. Based on this data, a practical diagnostic algorithm is proposed accounting for current molecular approaches, enzyme testing sensitivity, and variability due to gender, cell/tissue type used for testing, and successive repeat testing. Copyright © 2017 Elsevier Inc. All rights reserved.
CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.

PubMed

Lafarga, Vanesa; Tapia, Olga; Sharma, Sahil; Bengoechea, Rocio; Stoecklin, Georg; Lafarga, Miguel; Berciano, Maria T

2018-02-01

The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels.
The role of platelets during reproduction.

PubMed

Isermann, Berend; Nawroth, Peter P

2006-01-01

The availability of mice with defined defects within the hemostatic system enabled researchers to identify a role the coagulation system for embryonic and placental development. However, the role of platelets during development has only recently been experimentally addressed, giving some insight into potential functions of platelets during development. Thus, a quantitative embryonic platelet defect (severe thrombopenia secondary to NF-E2 deficiency) is associated with an embryonic growth retardation and reduced vascularisation of the placenta. Maternal platelet deficiency is associated with placental hemorrhage, which, however, does not impair embryonic or maternal survival. In vitro studies established that platelets or platelet conditioned medium regulate the invasive properties of human extravillous trophoblast cells and induce a phenotypical switch of trophoblast cells. These data imply that platelets are of relevance during placentation. Conversely, platelets and the formation of platelet-fibrin aggregates are dispensable for the development of the embryo proper, establishing that the lethal phenotypes observed in some embryo slacking coagulation regulators does not result from an inability to form platelet-fibrin aggregates, but likely reflects altered protease dependent signaling during vascular development.
Hybrid chickadees are deficient in learning and memory.

PubMed

McQuillan, Michael A; Roth, Timothy C; Huynh, Alex V; Rice, Amber M

2018-05-01

Identifying the phenotypes underlying postzygotic reproductive isolation is crucial for fully understanding the evolution and maintenance of species. One potential postzygotic isolating barrier that has rarely been examined is learning and memory ability in hybrids. Learning and memory are important fitness-related traits, especially in scatter-hoarding species, where accurate retrieval of hoarded food is vital for winter survival. Here, we test the hypothesis that learning and memory ability can act as a postzygotic isolating barrier by comparing these traits among two scatter-hoarding songbird species, black-capped (Poecile atricapillus) and Carolina chickadees (Poecile carolinensis), and their naturally occurring hybrids. In an outdoor aviary setting, we find that hybrid chickadees perform significantly worse on an associative learning spatial task and are worse at solving a novel problem compared to both parental species. Deficiencies in learning and memory abilities could therefore contribute to postzygotic reproductive isolation between chickadee species. Given the importance of learning and memory for fitness, our results suggest that these traits may play an important, but as yet overlooked, role in postzygotic reproductive isolation. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.
Iron deficiency anemia: diagnosis and management.

PubMed

Clark, Susan F

2009-03-01

Iron deficiency anemia (IDA) still remains universally problematic worldwide. The primary focus of this review is to critique articles published over the past 18 months that describe strategies for the diagnosis and management of this prevalent condition. The medical community continues to lack consensus when identifying the optimal approach for the diagnosis and management of IDA. Current diagnostic recommendations revolve around the validity and practicality of current biomarkers such as soluble transferrin-receptor concentrations and others, and cause-based diagnostics that potentially include endoscopy. Management of IDA is based on supplementation combined with effective etiological treatment. Advances in oral and parenteral low-molecular-weight iron preparations has expanded and improved treatment modalities for IDA. Since the introduction of low versus high-molecular-weight intravenous iron administration, there have been fewer serious adverse events associated with parenteral iron preparations. Best practice guidelines for diagnosing and managing IDA should include the design of an algorithm that is inclusive of multiple biomarkers and cause-based diagnostics, which will provide direction in managing IDA, and distinguish between IDA from the anemia of chronic disease.
Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

PubMed Central

Almeida, Sandra; Zhang, Zhijun; Coppola, Giovanni; Mao, Wenjie; Futai, Kensuke; Karydas, Anna; Geschwind, Michael D.; Tartaglia, M. Carmela; Gao, Fuying; Gianni, Davide; Sena-Esteves, Miguel; Geschwind, Daniel H.; Miller, Bruce L.; Farese, Robert V.; Gao, Fen-Biao

2012-01-01

SUMMARY The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell (iPSC) lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel GRN mutation (PGRN S116X). In neurons and microglia differentiated from PGRN S116X iPSCs, the levels of intracellular and secreted progranulin were reduced, establishing patient-specific cellular models of progranulin haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the PI3K and MAPK pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by progranulin expression. Our findings identify cell-autonomous, reversible defects in patient neurons with progranulin deficiency and provide a new model for studying progranulin-dependent pathogenic mechanisms and testing potential therapies. PMID:23063362
NONO couples the circadian clock to the cell cycle.

PubMed

Kowalska, Elzbieta; Ripperger, Juergen A; Hoegger, Dominik C; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A

2013-01-29

Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.
Determinants of Iron Deficiency Anemia in a Cohort of Children Aged 6-71 Months Living in the Northeast of Minas Gerais, Brazil

PubMed Central

Zanin, Francisca Helena Calheiros; da Silva, Camilo Adalton Mariano; Bonomo, Élido; Teixeira, Romero Alves; Pereira, Cíntia Aparecida de Jesus; dos Santos, Karina Benatti; Fausto, Maria Arlene; Negrão-Correa, Deborah Aparecida; Lamounier, Joel Alves; Carneiro, Mariângela

2015-01-01

Iron deficiency anemia is one of the most common nutritional disorders worldwide. The aim was to identify the prevalence and incidence of anemia in children and to identify predictors of this condition, including intestinal parasites, social, nutritional and environmental factors, and comorbidities. A population-based cohort study was conducted in a sample of 414 children aged 6–71 months living in Novo Cruzeiro in the Minas Gerais State. Data were collected in 2008 and 2009 by interview and included socio-economic and demographic information about the children and their families. Blood samples were collected for testing of hemoglobin, ferritin and C-reactive protein. Anthropometric measurements and parasitological analyses of fecal samples were performed. To identify risk factors associated with anemia multivariate analyses were performed using the generalized estimating equations (GEE). In 2008 and 2009, respectively, the prevalence rates of anemia were 35.9% (95%CI 31.2–40.8) and 9.8% (95%CI 7.2–12.9), the prevalence rates of iron deficiency were 18.4% (95%CI 14.7–22.6) and 21.8% (95%CI 17.8–26.2), and the incidence rates of anemia and iron deficiency were 3.2% and 21.8%. The following risk factors associated with anemia were: iron deficiency (OR = 3.2; 95%CI 2.0-.5.3), parasitic infections (OR = 1.9; 95%CI 1.2–2.8), being of risk of or being a low length/height-for-age (OR = 2.1; 95%CI 1.4–3.2), and lower retinol intake (OR = 1.7; 95%CI 1.1–2.7), adjusted over time. Nutritional factors, parasitic infections and chronic malnutrition were identified as risk factors for anemia. These factors can be verified in a chronic process and have been classically described as risk factors for these conditions. PMID:26445270
Determinants of Iron Deficiency Anemia in a Cohort of Children Aged 6-71 Months Living in the Northeast of Minas Gerais, Brazil.

PubMed

Zanin, Francisca Helena Calheiros; da Silva, Camilo Adalton Mariano; Bonomo, Élido; Teixeira, Romero Alves; Pereira, Cíntia Aparecida de Jesus; dos Santos, Karina Benatti; Fausto, Maria Arlene; Negrão-Correa, Deborah Aparecida; Lamounier, Joel Alves; Carneiro, Mariângela

2015-01-01

Iron deficiency anemia is one of the most common nutritional disorders worldwide. The aim was to identify the prevalence and incidence of anemia in children and to identify predictors of this condition, including intestinal parasites, social, nutritional and environmental factors, and comorbidities. A population-based cohort study was conducted in a sample of 414 children aged 6-71 months living in Novo Cruzeiro in the Minas Gerais State. Data were collected in 2008 and 2009 by interview and included socio-economic and demographic information about the children and their families. Blood samples were collected for testing of hemoglobin, ferritin and C-reactive protein. Anthropometric measurements and parasitological analyses of fecal samples were performed. To identify risk factors associated with anemia multivariate analyses were performed using the generalized estimating equations (GEE). In 2008 and 2009, respectively, the prevalence rates of anemia were 35.9% (95%CI 31.2-40.8) and 9.8% (95%CI 7.2-12.9), the prevalence rates of iron deficiency were 18.4% (95%CI 14.7-22.6) and 21.8% (95%CI 17.8-26.2), and the incidence rates of anemia and iron deficiency were 3.2% and 21.8%. The following risk factors associated with anemia were: iron deficiency (OR = 3.2; 95%CI 2.0-.5.3), parasitic infections (OR = 1.9; 95%CI 1.2-2.8), being of risk of or being a low length/height-for-age (OR = 2.1; 95%CI 1.4-3.2), and lower retinol intake (OR = 1.7; 95%CI 1.1-2.7), adjusted over time. Nutritional factors, parasitic infections and chronic malnutrition were identified as risk factors for anemia. These factors can be verified in a chronic process and have been classically described as risk factors for these conditions.
Cyclic Dipeptides from Bacillus vallismortis BS07 Require Key Components of Plant Immunity to Induce Disease Resistance in Arabidopsis against Pseudomonas Infection

PubMed Central

Noh, Seong Woo; Seo, Rira; Park, Jung-Kwon; Manir, Md. Maniruzzaman; Park, Kyungseok; Sang, Mee Kyung; Moon, Surk-Sik; Jung, Ho Won

2017-01-01

Cyclic dipeptides (CDPs) are one of the simplest compounds produced by living organisms. Plant-growth promoting rhizobacteria (PGPRs) also produce CDPs that can induce disease resistance. Bacillus vallismortis strain BS07 producing various CDPs has been evaluated as a potential biocontrol agent against multiple plant pathogens in chili pepper. However, plant signal pathway triggered by CDPs has not been fully elucidated yet. Here we introduce four CDPs, cyclo(Gly-L-Pro) previously identified from Aspergillus sp., and cyclo(L-Ala-L-Ile), cyclo(L-Ala-L-Leu), and cyclo(LLeu-L-Pro) identified from B. vallismortis BS07, which induce disease resistance in Arabidopsis against Pseudomonas syringae infection. The CDPs do not directly inhibit fungal and oomycete growth in vitro. These CDPs require PHYTOALEXIN DEFICIENT4, SALICYLIC ACID INDUCTION DEFICIENT2, and NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 important for salicylic acid-dependent defense to induce resistance. On the other hand, regulators involved in jasmonate-dependent event, such as ETHYLENE RECEPTOR1, JASMONATE RESPONSE1, and JASMONATE INSENSITIVE1, are necessary to the CDP-induced resistance. Furthermore, treatment of these CDPs primes Arabidopsis plants to rapidly express PATHOGENESIS-RELATED PROTEIN4 at early infection phase. Taken together, we propose that these CDPs from PGPR strains accelerate activation of jasmonate-related signaling pathway during infection. PMID:28811757
Potential roles of high salt intake and maternal malnutrition in the development of hypertension in disadvantaged populations.

PubMed

Thrift, Amanda G; Srikanth, Velandai; Fitzgerald, Sharyn M; Kalyanram, Kartik; Kartik, Kamakshi; Hoppe, Chantal C; Walker, Karen Z; Evans, Roger G

2010-02-01

1. It has been argued that all major risk factors for cardiovascular disease have been identified. Yet, epidemiological studies undertaken to identify risk factors have largely focused on populations in developed nations or on the urban or relatively affluent rural populations of developing countries. Poor rural populations are seldom studied. 2. Somewhat different risk factors may operate in poor rural populations. Evidence for this is provided by the finding that, in disadvantaged rural India, the prevalence of hypertension is greater than would be expected based on established risk factors in these populations. One risk factor to be considered is a poor intrauterine environment. 3. In animals, maternal macro- and micronutrient malnutrition can lead to reduced nephron endowment. Nephron deficiency, in turn, can render blood pressure salt sensitive. The combination of nephron deficiency and excessive salt intake will predispose to hypertension. 4. Human malnutrition may have similar effects, particularly in regions of the world where malnutrition is endemic and where women are disadvantaged by existing social practices. 5. Moreover, high salt intake is endemic in many parts of Asia, including India. Therefore, we propose that maternal malnutrition (leading to reduced nephron endowment), when combined with excessive salt intake postnatally, will account, at least in part, for the unexpectedly high prevalence of hypertension in disadvantaged rural communities in India and elsewhere.
Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

PubMed Central

Kim, Kyung-Jin; Pearl, Phillip L.; Jensen, Kimmo; Snead, O. Carter; Malaspina, Patrizia; Jakobs, Cornelis

2011-01-01

Abstract Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691–718. PMID:20973619

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