Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-04-15

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis. The enhanced hepatic glycolysis is reflected by increased lactate accumulation, increased expression of many glycolytic enzymes, and elevated expression of c-Myc that stimulates glycolysis. The increased HMS is reflected by increased glucose-6-phosphate dehydrogenase activity and elevated production of NADPH and the reduced glutathione. We have previously shown that restoration of hepatic G6Pase-α expression in G6Pase-α-deficient liver corrects metabolic abnormalities, normalizes autophagy, and prevents HCA/HCC development in GSD-Ia. We now show that restoration of hepatic G6Pase-α expression normalizes both glycolysis and HMS in GSD-Ia. Moreover, the HCA/HCC lesions in L-G6pc-/- mice exhibit elevated levels of hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) which play an important role in aerobic glycolysis and cancer cell proliferation. Taken together, hepatic G6Pase-α deficiency causes metabolic reprogramming, leading to enhanced glycolysis and elevated HMS that along with impaired autophagy can contribute to HCA/HCC development in GSD-Ia. Published by Elsevier Inc.

B12 deficiency leading to marked poikilocytosis versus true schistocytosis, a pernicious problem.

PubMed

Hall, James A; Mason, James; Choi, Julia; Holguin, Mark

2017-08-01

Severe vitamin B12 deficiency is caused most commonly by autoimmune atrophic gastritis leading to loss of intrinsic factor. Vitamin B12 deficiency leading to megaloblastic anemia and demyelinating central nervous system disease is well known; however, a rare presentation of B12 deficiency described as pseudothrombotic microangiopathy is not well known. This complication presents with signs of mechanical hemolysis, elevated lactate dehydrogenase (LDH), thrombocytopenia, and a low reticulocyte count, which can be incorrectly diagnosed as thrombotic thrombocytopenic purpura and managed incorrectly. Decreased reticulocyte count and an LDH >2500IU/L is more commonly seen in B12 deficiency. However, recognizing the differences in marked poikilocytosis can be challenging, as seen with megaloblastic changes and true schistocytosis. To illustrate the challenge in differentiating between megaloblastic changes and true schistocytosis, we present the case of a 27-year-old woman who presented to her physician for symptomatic anemia and complaints of nausea, vomiting, and loose stool. She had a hemoglobin of 5.1g/dL, platelet count of 39×10 9 /L, LDH of 9915IU/L, haptoglobin below assay limit, and a reticulocyte count of 2.5%. Peripheral smear showed macrocytic anemia, rare hypersegmented neutrophils, and schistocytes. Vitamin B12 level was less than 50pg/mL, methylmalonic acid was 0.33μmol/L, anti-parietal cell antibody was >1:640, and intrinsic factor blocking antibody was positive-confirming the diagnosis of pernicious anemia. While hospitalized, she was treated with vitamin B12 1000μg intramuscular injections daily and thereafter continued with monthly injections, which ultimately resolved her severe macrocytic anemia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of cellular MMP substrates using quantitative proteomics: isotope-coded affinity tags (ICAT) and isobaric tags for relative and absolute quantification (iTRAQ).

PubMed

Butler, Georgina S; Dean, Richard A; Morrison, Charlotte J; Overall, Christopher M

2010-01-01

Identification of protease substrates is essential to understand the functional consequences of normal proteolytic processing and dysregulated proteolysis in disease. Quantitative proteomics and mass spectrometry can be used to identify protease substrates in the cellular context. Here we describe the use of two protein labeling techniques, Isotope-Coded Affinity Tags (ICAT and Isobaric Tags for Relative and Absolute Quantification (iTRAQ), which we have used successfully to identify novel matrix metalloproteinase (MMP) substrates in cell culture systems (1-4). ICAT and iTRAQ can label proteins and protease cleavage products of secreted proteins, protein domains shed from the cell membrane or pericellular matrix of protease-transfected cells that have accumulated in conditioned medium, or cell surface proteins in membrane preparations; isotopically distinct labels are used for control cells. Tryptic digestion and tandem mass spectrometry of the generated fragments enable sequencing of differentially labeled but otherwise identical pooled peptides. The isotopic tag, which is unique for each label, identifies the peptides originating from each sample, for instance, protease-transfected or control cells, and comparison of the peak areas enables relative quantification of the peptide in each sample. Thus proteins present in altered amounts between protease-expressing and null cells are implicated as protease substrates and can be further validated as such.

Sema4D/CD100 deficiency leads to superior performance in mouse motor behavior.

PubMed

Yukawa, Kazunori; Tanaka, Tetsuji; Takeuchi, Noriko; Iso, Hiroyuki; Li, Li; Kohsaka, Akira; Waki, Hidefumi; Miyajima, Masayasu; Maeda, Masanobu; Kikutani, Hitoshi; Kumanogoh, Atsushi

2009-05-01

Sema4D/CD100 is a type of class 4 semaphorin, exhibiting crucial roles in growth cone guidance in developing neurons. Sema4D is widely expressed throughout the central nervous system in embryonic mouse brain, and is selectively localized to oligodendrocytes and myelin in the postnatal brain. However, direct evidence of the actual involvement of Sema4D in the neuronal network development crucial for neurobehavioral performance is still lacking. The present study therefore examined whether Sema4D deficiency leads to abnormal behavioral development. Both wild-type and Sema4D-deficient mice were subjected to behavioral analyses including open-field, adhesive tape removal, rotarod tests and a water maze task. Open-field tests revealed increased locomotor activity in Sema4D-deficient mice with less percentage of time spent in the center of the field. In both the adhesive tape removal and rotarod tests, which examine motor coordination and balance, Sema4D-deficient mice showed significantly superior performance, suggesting facilitated motor behavior. Both Sema4D-deficient and wild-type mice successfully learnt the water maze task, locating a hidden escape platform, and also showed precise memory for the platform position in probe tests. However, the swimming speed of Sema4D-deficient mice was significantly faster than that of wild-type mice, providing further evidence of their accelerated motor behavior. Our mouse behavioral analyses revealed enhanced motor activity in Sema4D-deficient mice, suggesting the crucial involvement of Sema4D in the neurodevelopmental processes of the central structures mediating motor behavior in mice.

Dosimetry of 3 CBCT devices for oral and maxillofacial radiology: CB Mercuray, NewTom 3G and i-CAT.

PubMed

Ludlow, J B; Davies-Ludlow, L E; Brooks, S L; Howerton, W B

2006-07-01

Cone beam computed tomography (CBCT), which provides a lower dose, lower cost alternative to conventional CT, is being used with increasing frequency in the practice of oral and maxillofacial radiology. This study provides comparative measurements of effective dose for three commercially available, large (12'') field-of-view (FOV), CBCT units: CB Mercuray, NewTom 3G and i-CAT. Thermoluminescent dosemeters (TLDs) were placed at 24 sites throughout the layers of the head and neck of a tissue-equivalent human skull RANDO phantom. Depending on availability, the 12'' FOV and smaller FOV scanning modes were used with similar phantom positioning geometry for each CBCT unit. Radiation weighted doses to individual organs were summed using 1990 (E(1990)) and proposed 2005 (E(2005 draft)) ICRP tissue weighting factors to calculate two measures of whole-body effective dose. Dose as a multiple of a representative panoramic radiography dose was also calculated. For repeated runs dosimetry was generally reproducible within 2.5%. Calculated doses in microSv [corrected] (E(1990), E(2005 draft)) were NewTom3G (45, 59), i-CAT (135, 193) and CB Mercuray (477, 558). These are 4 to 42 times greater than comparable panoramic examination doses (6.3 microSv [corrected] 13.3 mSv). Reductions in dose were seen with reduction in field size and mA and kV technique factors. CBCT dose varies substantially depending on the device, FOV and selected technique factors. Effective dose detriment is several to many times higher than conventional panoramic imaging and an order of magnitude or more less than reported doses for conventional CT.

MiR-424-5p reversed epithelial-mesenchymal transition of anchorage-independent HCC cells by directly targeting ICAT and suppressed HCC progression

PubMed Central

Zhang, Ying; Li, Tao; Guo, Pengbo; Kang, Jia; Wei, Qing; Jia, Xiaoqing; Zhao, Wei; Huai, Wanwan; Qiu, Yumin; Sun, Lei; Han, Lihui

2014-01-01

Resistance to anoikis and Epithelial-mesenchymal transition (EMT) are two processes critically involved in cancer metastasis. In this study, we demonstrated that after anchorage deprival, hepatocellular carcinoma (HCC) cells not only resisted anoikis, but also exhibited EMT process. Microarray expression profiling revealed that expression of miR-424-5p was significantly decreased in anoikis-resistant HCC cells. Ectopic overexpression of miR-424-5p was sufficient to reverse resistance to anoikis, block EMT process and inhibit malignant behaviors of HCC cells. Target analysis showed that a potent β-catenin inhibitor, ICAT/CTNNBIP1 was a direct target of miR-424-5p. Further study demonstrated that miR-424-5p reversed resistance to anoikis and EMT of HCCs by directly targeting ICAT and further maintaining the E-cadherin/β-catanin complex on the cellular membrance. In vivo study further demonstrated that miR-424-5p significantly inhibited the tumorigenicity of HCC cells in nude mice. Clinical investigation demonstrated that miR-424-5p was significantly downregulated in HCC tissues compared with that of the non-cancerous liver tissues, and this decreased expression of miR-424-5p was significantly correlated with higher pathological grades and more advanced TNM stages. Therefore, aberrant expression of miR-424-5p is critically involved in resistance to anoikis and EMT during the metastatic process of HCC, and its downregulation significantly contributes to liver cancer progression. PMID:25175916

GRK5 deficiency leads to susceptibility to intermittent hypoxia-induced cognitive impairment.

PubMed

Singh, Prabhakar; Peng, Wei; Zhang, Qiang; Ding, XueFeng; Suo, William Z

2016-04-01

Obstructive sleep apnea (OSA) leads to cognitive impairment in about 25% patients, though it remains elusive what makes one more susceptible than the other to be cognitively impaired. G protein-coupled receptor kinase-5 (GRK5) deficiency is recently found to render subjects more susceptible to cognitive impairment triggered by over-expression of Swedish mutant ß-amyloid precursor protein. This study is to determine whether GRK5 deficiency also renders subjects more susceptible to the OSA-triggered cognitive impairment. Both wild type (WT) and GRK5 knockout (KO) mice were placed in conditions absence and presence of intermittent hypoxia (IH) with 8%/21% O2 90-s cycle for 8h a day for a month, and then followed by behavioral assessments with battery of tasks. We found that the selected IH condition only induced marginally abnormal behavior (slightly elevated anxiety with most others unchanged) in the WT mice but it caused significantly more behavioral deficits in the KO mice, ranging from elevated anxiety, impaired balancing coordination, and impaired short-term spatial memory. These results suggest that GRK5 deficiency indeed makes the mice more susceptible to wide range of behavioral impairments, including cognitive impairments. Published by Elsevier B.V.

ISS Mini AERCam Radio Frequency (RF) Coverage Analysis Using iCAT Development Tool

NASA Technical Reports Server (NTRS)

Bolen, Steve; Vazquez, Luis; Sham, Catherine; Fredrickson, Steven; Fink, Patrick; Cox, Jan; Phan, Chau; Panneton, Robert

2003-01-01

The long-term goals of the National Aeronautics and Space Administration's (NASA's) Human Exploration and Development of Space (HEDS) enterprise may require the development of autonomous free-flier (FF) robotic devices to operate within the vicinity of low-Earth orbiting spacecraft to supplement human extravehicular activities (EVAs) in space. Future missions could require external visual inspection of the spacecraft that would be difficult, or dangerous, for humans to perform. Under some circumstance, it may be necessary to employ an un-tethered communications link between the FF and the users. The interactive coverage analysis tool (ICAT) is a software tool that has been developed to perform critical analysis of the communications link performance for a FF operating in the vicinity of the International Space Station (ISS) external environment. The tool allows users to interactively change multiple parameters of the communications link parameters to efficiently perform systems engineering trades on network performance. These trades can be directly translated into design and requirements specifications. This tool significantly reduces the development time in determining a communications network topology by allowing multiple parameters to be changed, and the results of link coverage to be statistically characterized and plotted interactively.

Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease

PubMed Central

Cario, Holger; Smith, Desirée E.C.; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

2011-01-01

The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. PMID:21310277

[Expression of ICAT and Wnt signaling-related proteins in the monocytic differentiation of HL-60 cells induced by a new steroidal drug NSC67657].

PubMed

Wang, J S; Wang, W J; Wang, T; Zhang, Y

2016-04-01

To investigate the expression of mRNA and proteins of β-catenin, TCF-4 (ICAT) and Wnt signaling pathway-related genes in the monocytic differentiation of acute myeloid leukemia HL-60 cells induced by a new steroidal drug NSC67657. Wright's staining and α-NBE staining were used to observe the differentiation of HL-60 cells after 5 days of 10 μmol/L NSC67657 treatment. Flow cytometry (FCM) was used to detect the differentiation and cell cycles. The expressions of mRNA and proteins of ICAT and Wnt signaling pathway-related factors, including β-catenin, TCF-4, c-myc, cyclin D1 and TCF-1 before and after differentiation, were detected by RT-PCR and Western blot. Morphological observation showed that NSC67657 induced monocytic differentiation of HL-60 cells. At 5 days after 10 μmol/L NSC67657 treatment, the number of CD14(+) HL-60 cells was (94.37±2.84)%, significantly higher than the (1.31±0.09)% in control group (P<0.01). The flow cytometry assay revealed that NSC67657 induced (76.46±2.83)% of G1/G0 phase arrest, significantly higher than that of (59.40±5.42)% in the control group (P<0.05), while the S phase cells were of (18.76±0.98)%, significantly lower than that of (34.38±2.61) % in the control group (P<0.05). The NSC67657 treatment also up-regulated the expression of ICAT mRNA and protein, and down-regulated the expression of β-catenin mRNA and protin (P<0.01 for all). However, the nuclear expression of β-catenin was down-regulated (P<0.01). The NSC67657 treatment induced nonsignificant alterations of TCF-4 mRNA, total protein and nuclear protein in the HL-60 cells (P>0.05 for all). The target genes of Wnt signaling pathway, including c-myc, cyclinD1 and TCF-1 mRNA and proteins in the HL-60 cells were significantly down-regulated after NSC67657 treatment (P<0.05). The new steroidal drug NSC67657 induces monocytic differentiation of HL-60 cells, and down-regulates the expression of β-catenin and target genes of Wnt signaling pathway. These results

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior.

PubMed

Li, Yan; Yin, Anqi; Sun, Xin; Zhang, Ming; Zhang, Jianfang; Wang, Ping; Xie, Rougang; Li, Wen; Fan, Ze; Zhu, Yuanyuan; Wang, Han; Dong, Hailong; Wu, Shengxi; Xiong, Lize

2017-12-01

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder in children. Although an imbalance of excitatory and inhibitory inputs has been proposed as contributing to this disorder, the mechanisms underlying this highly heterogeneous disease remain largely unknown. Here, we show that N-myc downstream-regulated gene 2 (NDRG2) deficiency is involved in the development of ADHD in both mice and humans. Ndrg2-knockout (Ndrg2-/-) mice exhibited ADHD-like symptoms characterized by attention deficits, hyperactivity, impulsivity, and impaired memory. Furthermore, interstitial glutamate levels and excitatory transmission were markedly increased in the brains of Ndrg2-/- mice due to reduced astroglial glutamate clearance. We developed an NDRG2 peptide that rescued astroglial glutamate clearance and reduced excitatory glutamate transmission in NDRG2-deficient astrocytes. Additionally, NDRG2 peptide treatment rescued ADHD-like hyperactivity in the Ndrg2-/- mice, while routine methylphenidate treatment had no effect on hyperactivity in these animals. Finally, children who were heterozygous for rs1998848, a SNP in NDRG2, had a higher risk of ADHD than children who were homozygous for rs1998848. Our results indicate that NDRG2 deficiency leads to ADHD phenotypes and that impaired astroglial glutamate clearance, a mechanism distinct from the well-established dopamine deficit hypothesis for ADHD, underlies the resultant behavioral abnormalities.

Vitamin B12 deficiency results in severe oxidative stress, leading to memory retention impairment in Caenorhabditis elegans.

PubMed

Bito, Tomohiro; Misaki, Taihei; Yabuta, Yukinori; Ishikawa, Takahiro; Kawano, Tsuyoshi; Watanabe, Fumio

2017-04-01

Oxidative stress is implicated in various human diseases and conditions, such as a neurodegeneration, which is the major symptom of vitamin B 12 deficiency, although the underlying disease mechanisms associated with vitamin B 12 deficiency are poorly understood. Vitamin B 12 deficiency was found to significantly increase cellular H 2 O 2 and NO content in Caenorhabditis elegans and significantly decrease low molecular antioxidant [reduced glutathione (GSH) and L-ascorbic acid] levels and antioxidant enzyme (superoxide dismutase and catalase) activities, indicating that vitamin B 12 deficiency induces severe oxidative stress leading to oxidative damage of various cellular components in worms. An NaCl chemotaxis associative learning assay indicated that vitamin B 12 deficiency did not affect learning ability but impaired memory retention ability, which decreased to approximately 58% of the control value. When worms were treated with 1mmol/L GSH, L-ascorbic acid, or vitamin E for three generations during vitamin B 12 deficiency, cellular malondialdehyde content as an index of oxidative stress decreased to the control level, but the impairment of memory retention ability was not completely reversed (up to approximately 50%). These results suggest that memory retention impairment formed during vitamin B 12 deficiency is partially attributable to oxidative stress. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

PubMed

Cario, Holger; Smith, Desirée E C; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

2011-02-11

The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish.

PubMed

Bühler, Anja; Kustermann, Monika; Bummer, Tiziana; Rottbauer, Wolfgang; Sandri, Marco; Just, Steffen

2016-01-30

Orchestrated protein synthesis and degradation is fundamental for proper cell function. In muscle, impairment of proteostasis often leads to severe cellular defects finally interfering with contractile function. Here, we analyze for the first time the role of Atrogin-1, a muscle-specific E3 ubiquitin ligase known to be involved in the regulation of protein degradation via the ubiquitin proteasome and the autophagy/lysosome systems, in the in vivo model system zebrafish (Danio rerio). We found that targeted inactivation of zebrafish Atrogin-1 leads to progressive impairment of heart and skeletal muscle function and disruption of muscle structure without affecting early cardiogenesis and skeletal muscle development. Autophagy is severely impaired in Atrogin-1-deficient zebrafish embryos resulting in the disturbance of the cytoarchitecture of cardiomyocytes and skeletal muscle cells. These observations are consistent with molecular and ultrastructural findings in an Atrogin-1 knockout mouse and demonstrate that the zebrafish is a suitable vertebrate model to study the molecular mechanisms of Atrogin-1-mediated autophagic muscle pathologies and to screen for novel therapeutically active substances in high-throughput in vivo small compound screens (SCS).

DNA-PKcs deficiency leads to persistence of oxidatively-induced clustered DNA lesions in human tumor cells

PubMed Central

Peddi, Prakash; Loftin, Charles W.; Dickey, Jennifer S.; Hair, Jessica M.; Burns, Kara J.; Aziz, Khaled; Francisco, Dave C.; Panayiotidis, Mihalis I.; Sedelnikova, Olga A.; Bonner, William M.; Winters, Thomas A.; Georgakilas, Alexandros G.

2010-01-01

DNA-dependent protein kinase (DNA-PK) is a key non-homologous end joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. In order to examine the role of DNA-PK in processing of non-DSB clustered DNA damage, we have used three different models of DNA-PK deficiency i.e. chemical inactivation of its kinase activity by novel inhibitors IC86621 and NU7026, knock-down and complete absence of the protein in human breast cancer (MCF-7) and glioblastoma cell lines (MO59-J/K). Compromised DNA-PK repair pathway has lead to accumulation of clustered DNA lesions induced by γ-rays. Tumor cells lacking protein expression or with inhibited kinase activity showed a marked decrease in their ability to process oxidatively-induced non-DSB clustered DNA lesions measured using a modified version of pulsed field gel electrophoresis or single cell gel electrophoresis (Comet assay). In all cases, DNA-PK inactivation lead to a higher level of lesion persistence even after 24–72 hrs of repair. We suggest a model in which DNA-PK deficiency affects the processing of these clusters by first compromising base excision repair and second by the presence of catalytically inactive DNA-PK inhibiting the efficient processing of these lesions due to the failure of DNA-PK to disassociate from the DNA ends. The information rendered will be important not only for understating cancer etiology in the presence of a NHEJ deficiency but also lead to a better understanding of cancer treatments based on the induction of oxidative stress and inhibition of cluster repair. PMID:20193758

Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

PubMed

Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

2013-01-01

Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect β-Oxidation

PubMed Central

von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

2013-01-01

Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2−/−) that progressively loses its mtDNA. The TK2−/− mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2−/− mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2−/− mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2−/− mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2−/− mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies. PMID:23505564

Ascorbic acid deficiency leads to increased grain chalkiness in transgenic rice for suppressed of L-GalLDH.

PubMed

Yu, Le; Liu, Yonghai; Lu, Lina; Zhang, Qilei; Chen, Yezheng; Zhou, Liping; Chen, Hua; Peng, Changlian

2017-04-01

The grain chalkiness of rice (Oryza sativa L.), which determines the rice quality and price, is a major concern in rice breeding. Reactive oxygen species (ROS) plays a critical role in regulating rice endosperm chalkiness. Ascorbic acid (Asc) is a major plant antioxidant, which strictly regulates the levels of ROS. l-galactono-1, 4-lactone dehydrogenase (L-GalLDH, EC 1.3.2.3) is an enzyme that catalyzes the last step of Asc biosynthesis in higher plants. Here we show that the L-GalLDH-suppressed transgenic rice, GI-1 and GI-2, which have constitutively low (between 30% and 50%) leaf and grain Asc content compared with the wild-type (WT), exhibit significantly increased grain chalkiness. Further examination showed that the deficiency of Asc resulted in a higher lipid peroxidation and H 2 O 2 content, accompanied by a lower hydroxyl radical scavenging rate, total antioxidant capacity and photosynthetic ability. In addition, changes of the enzyme activities and gene transcript abundances related to starch synthesis were also observed in GI-1 and GI-2 grains. The results we presented here suggest a close correlation between Asc deficiency and grain chalkiness in the L-GalLDH-suppressed transgenics. Asc deficiency leads to the accumulation of H 2 O 2 , affecting antioxidant capacity and photosynthetic function, changing enzyme activities and gene transcript abundances related to starch synthesis, finally leading to the increased grain chalkiness. Copyright © 2017 Elsevier GmbH. All rights reserved.

Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2α and Altered Expression of Iron Absorption Genes in Mice

PubMed Central

Matak, Pavle; Zumerle, Sara; Mastrogiannaki, Maria; El Balkhi, Souleiman; Delga, Stephanie; Mathieu, Jacques R. R.; Canonne-Hergaux, François; Poupon, Joel; Sharp, Paul A.; Vaulont, Sophie; Peyssonnaux, Carole

2013-01-01

Iron and copper are essential trace metals, actively absorbed from the proximal gut in a regulated fashion. Depletion of either metal can lead to anemia. In the gut, copper deficiency can affect iron absorption through modulating the activity of hephaestin - a multi-copper oxidase required for optimal iron export from enterocytes. How systemic copper status regulates iron absorption is unknown. Mice were subjected to a nutritional copper deficiency-induced anemia regime from birth and injected with copper sulphate intraperitoneally to correct the anemia. Copper deficiency resulted in anemia, increased duodenal hypoxia and Hypoxia inducible factor 2α (HIF-2α) levels, a regulator of iron absorption. HIF-2α upregulation in copper deficiency appeared to be independent of duodenal iron or copper levels and correlated with the expression of iron transporters (Ferroportin - Fpn, Divalent Metal transporter – Dmt1) and ferric reductase – Dcytb. Alleviation of copper-dependent anemia with intraperitoneal copper injection resulted in down regulation of HIF-2α-regulated iron absorption genes in the gut. Our work identifies HIF-2α as an important regulator of iron transport machinery in copper deficiency. PMID:23555700

[Small airway diseases and immune deficiency].

PubMed

Burgel, P-R; Bergeron, A; Knoop, C; Dusser, D

2016-02-01

Innate or acquired immune deficiency may show respiratory manifestations, often characterized by small airway involvement. The purpose of this article is to provide an overview of small airway disease across the major causes of immune deficiency. In patients with common variable immune deficiency, recurrent lower airway infections may lead to bronchiolitis and bronchiectasis. Follicular and/or granulomatous bronchiolitis of unknown origin may also occur. Bronchiolitis obliterans is the leading cause of death after the first year in patients with lung transplantation. Bronchiolitis obliterans also occurs in patients with allogeneic haematopoietic stem cell transplantation, especially in the context of systemic graft-versus-host disease. Small airway diseases have different clinical expression and pathophysiology across various causes of immune deficiency. A better understanding of small airways disease pathogenesis in these settings may lead to the development of novel targeted therapies. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

PubMed Central

Grond, Susanne; Eichmann, Thomas O.; Dubrac, Sandrine; Kolb, Dagmar; Schmuth, Matthias; Fischer, Judith; Crumrine, Debra; Elias, Peter M.; Haemmerle, Guenter; Zechner, Rudolf; Lass, Achim; Radner, Franz P.W.

2017-01-01

Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency. PMID:27751867

Study of the scan uniformity from an i-CAT cone beam computed tomography dental imaging system.

PubMed

Bryant, J A; Drage, N A; Richmond, S

2008-10-01

As part of an ongoing programme to improve diagnosis and treatment planning relevant to implant placement, orthodontic treatment and dentomaxillofacial surgery, a study has been made of the spatial accuracy and density response of an i-CAT, a cone beam CT (CBCT) dental imaging system supplied by Imaging Sciences International Inc. Custom-made phantoms using acrylic sheet and water were used for measurements on spatial accuracy, density response and noise. The measurements were made over a period of several months on a clinical machine rather than on a machine dedicated to research. Measurements on a precision grid showed the spatial accuracy to be universally within the tolerance of +/-1 pixel. The density response and the noise in the data were found to depend strongly on the mass in the slice being scanned. The density response was subject to two effects. The first effect changes the whole slice uniformly and linearly depends on the total mass in the slice. The second effect exists when there is mass outside the field of view, dubbed the "exo-mass" effect. This effect lowers the measured CT number rapidly at the scan edge furthest from the exo-mass and raises it on the adjacent edge. The noise also depended quasi-linearly on the mass in the slice. Some general performance rules were drafted to describe these effects and a preliminary correction algorithm was constructed.

Phantom dosimetry and image quality of i-CAT FLX cone-beam computed tomography

PubMed Central

Ludlow, John B.; Walker, Cameron

2013-01-01

Introduction Increasing use of cone-beam computed tomography in orthodontics has been coupled with heightened concern with the long-term risks of x-ray exposure in orthodontic populations. An industry response to this has been to offer low-exposure alternative scanning options in newer cone-beam computed tomography models. Methods Effective doses resulting from various combinations of field size, and field location comparing child and adult anthropomorphic phantoms using the recently introduced i-CAT FLX cone-beam computed tomography unit were measured with Optical Stimulated Dosimetry using previously validated protocols. Scan protocols included High Resolution (360° rotation, 600 image frames, 120 kVp, 5 mA, 7.4 sec), Standard (360°, 300 frames, 120 kVp, 5 mA, 3.7 sec), QuickScan (180°, 160 frames, 120 kVp, 5 mA, 2 sec) and QuickScan+ (180°, 160 frames, 90 kVp, 3 mA, 2 sec). Contrast-to-noise ratio (CNR) was calculated as a quantitative measure of image quality for the various exposure options using the QUART DVT phantom. Results Child phantom doses were on average 36% greater than Adult phantom doses. QuickScan+ protocols resulted in significantly lower doses than Standard protocols for child (p=0.0167) and adult (p=0.0055) phantoms. 13×16 cm cephalometric fields of view ranged from 11–85 μSv in the adult phantom and 18–120 μSv in the child for QuickScan+ and Standard protocols respectively. CNR was reduced by approximately 2/3rds comparing QuickScan+ to Standard exposure parameters. Conclusions QuickScan+ effective doses are comparable to conventional panoramic examinations. Significant dose reductions are accompanied by significant reductions in image quality. However, this trade-off may be acceptable for certain diagnostic tasks such as interim assessment of treatment results. PMID:24286904

Glucose-6-phosphate dehydrogenase deficiency.

PubMed

Cappellini, M D; Fiorelli, G

2008-01-05

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide. The global distribution of this disorder is remarkably similar to that of malaria, lending support to the so-called malaria protection hypothesis. G6PD deficiency is an X-linked, hereditary genetic defect due to mutations in the G6PD gene, which cause functional variants with many biochemical and clinical phenotypes. About 140 mutations have been described: most are single base changes, leading to aminoacid substitutions. The most frequent clinical manifestations of G6PD deficiency are neonatal jaundice, and acute haemolytic anaemia, which is usually triggered by an exogenous agent. Some G6PD variants cause chronic haemolysis, leading to congenital non-spherocytic haemolytic anaemia. The most effective management of G6PD deficiency is to prevent haemolysis by avoiding oxidative stress. Screening programmes for the disorder are undertaken, depending on the prevalence of G6PD deficiency in a particular community.

Genetics Home Reference: familial glucocorticoid deficiency

MedlinePlus

... familial glucocorticoid deficiency type 1 lead to defective trafficking of the receptor to the cell surface. J ... short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012 Mar;122(3):814- ...

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.

PubMed

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas D E; Rozen, Rima

2015-03-01

Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot

Haploinsufficiency of E-selectin ligand-1 is Associated with Reduced Atherosclerotic Plaque Macrophage Content while Complete Deficiency Leads to Early Embryonic Lethality in Mice

PubMed Central

Luo, Wei; Wang, Hui; Guo, Chiao; Wang, Jintao; Kwak, Jeffrey; Bahrou, Kristina L; Eitzman, Daniel T.

2012-01-01

E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-β complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1+/-) were intercrossed to produce ESL-1-/- mice, however ESL-1-/- mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE-/-), ESL-1+/- mice were generated and fed western diet. Compared to ApoE-/-, ESL-1++ mice, atherosclerotic lesions from ApoE-/-, ESL-1+/- contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality. PMID:22939356

Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

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

Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert

Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinalmore » microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.« less

Proceedings of the 1993 Conference on Intelligent Computer-Aided Training and Virtual Environment Technology, Volume 1

NASA Technical Reports Server (NTRS)

Hyde, Patricia R.; Loftin, R. Bowen

1993-01-01

These proceedings are organized in the same manner as the conference's contributed sessions, with the papers grouped by topic area. These areas are as follows: VE (virtual environment) training for Space Flight, Virtual Environment Hardware, Knowledge Aquisition for ICAT (Intelligent Computer-Aided Training) & VE, Multimedia in ICAT Systems, VE in Training & Education (1 & 2), Virtual Environment Software (1 & 2), Models in ICAT systems, ICAT Commercial Applications, ICAT Architectures & Authoring Systems, ICAT Education & Medical Applications, Assessing VE for Training, VE & Human Systems (1 & 2), ICAT Theory & Natural Language, ICAT Applications in the Military, VE Applications in Engineering, Knowledge Acquisition for ICAT, and ICAT Applications in Aerospace.

Both Selenium Deficiency and Modest Selenium Supplementation Lead to Myocardial Fibrosis in Mice via Effects on Redox-Methylation Balance

PubMed Central

Metes-Kosik, Nicole; Luptak, Ivan; DiBello, Patricia M.; Handy, Diane E.; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W.; Loscalzo, Joseph; Joseph, Jacob

2013-01-01

Scope Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. Methods and Results We examined the effects of selenium deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Conclusions Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. PMID:23097236

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

PubMed Central

Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

2015-01-01

Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/− mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/− mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/− livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/− mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2

Congenital deficiency of alpha feto-protein.

PubMed

Sharony, Reuven; Zadik, Idit; Parvari, Ruti

2004-10-01

Alpha-fetoprotein (AFP) is the main fetus serum glycoprotein with a very low concentration in the adult. AFP deficiency is a rare phenomenon. We studied two families with congenital AFP deficiency and searched for mutations in the AFP gene. We identified one mutation of 2 base deletion in exon 8, in both families, that leads to the congenital deficiency of AFP. The mutation nt930-931delCT (T294fs25X) creates a frameshift after codon 294 that leads to a stop codon after 24 amino acids, thus truncating the normal length of AFP of 609 amino acids. All the affected children were found to be homozygous for the mutation as was one of the fathers. The affected individuals were asymptomatic and presented normal development. This first identification of a mutation in the AFP gene demonstrates for the first time that deficiency of AFP is compatible with human normal fetal development and further reproduction in males.

Thiol peroxidase deficiency leads to increased mutational load and decreased fitness in Saccharomyces cerevisiae.

PubMed

Kaya, Alaattin; Lobanov, Alexei V; Gerashchenko, Maxim V; Koren, Amnon; Fomenko, Dmitri E; Koc, Ahmet; Gladyshev, Vadim N

2014-11-01

Thiol peroxidases are critical enzymes in the redox control of cellular processes that function by reducing low levels of hydroperoxides and regulating redox signaling. These proteins were also shown to regulate genome stability, but how their dysfunction affects the actual mutations in the genome is not known. Saccharomyces cerevisiae has eight thiol peroxidases of glutathione peroxidase and peroxiredoxin families, and the mutant lacking all these genes (∆8) is viable. In this study, we employed two independent ∆8 isolates to analyze the genome-wide mutation spectrum that results from deficiency in these enzymes. Deletion of these genes was accompanied by a dramatic increase in point mutations, many of which clustered in close proximity and scattered throughout the genome, suggesting strong mutational bias. We further subjected multiple lines of wild-type and ∆8 cells to long-term mutation accumulation, followed by genome sequencing and phenotypic characterization. ∆8 lines showed a significant increase in nonrecurrent point mutations and indels. The original ∆8 cells exhibited reduced growth rate and decreased life span, which were further reduced in all ∆8 mutation accumulation lines. Although the mutation spectrum of the two independent isolates was different, similar patterns of gene expression were observed, suggesting the direct contribution of thiol peroxidases to the observed phenotypes. Expression of a single thiol peroxidase could partially restore the growth phenotype of ∆8 cells. This study shows how deficiency in nonessential, yet critical and conserved oxidoreductase function, leads to increased mutational load and decreased fitness. Copyright © 2014 by the Genetics Society of America.

Structural distortions due to missense mutations in human formylglycine-generating enzyme leading to multiple sulfatase deficiency.

PubMed

Meshach Paul, D; Chadah, Tania; Senthilkumar, B; Sethumadhavan, Rao; Rajasekaran, R

2017-11-03

The major candidate for multiple sulfatase deficiency is a defective formylglycine-generating enzyme (FGE). Though adequately produced, mutations in FGE stall the activation of sulfatases and prevent their activity. Missense mutations, viz. E130D, S155P, A177P, W179S, C218Y, R224W, N259I, P266L, A279V, C336R, R345C, A348P, R349Q and R349W associated with multiple sulfatase deficiency are yet to be computationally studied. Aforementioned mutants were initially screened through ws-SNPs&GO 3D program. Mutant R345C acquired the highest score, and hence was studied in detail. Discrete molecular dynamics explored structural distortions due to amino acid substitution. Therein, comparative analyses of wild type and mutant were carried out. Changes in structural contours were observed between wild type and mutant. Mutant had low conformational fluctuation, high atomic mobility and more compactness than wild type. Moreover, free energy landscape showed mutant to vary in terms of its conformational space as compared to wild type. Subsequently, wild type and mutant were subjected to single-model analyses. Mutant had lesser intra molecular interactions than wild type suggesting variations pertaining to its secondary structure. Furthermore, simulated thermal denaturation showed dissimilar pattern of hydrogen bond dilution. Effects of these variations were observed as changes in elements of secondary structure. Docking studies of mutant revealed less favourable binding energy towards its substrate as compared to wild type. Therefore, theoretical explanations for structural distortions of mutant R345C leading to multiple sulfatase deficiency were revealed. The protocol of the study could be useful to examine the effectiveness of pharmacological chaperones prior to experimental studies.

Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance.

PubMed

Metes-Kosik, Nicole; Luptak, Ivan; Dibello, Patricia M; Handy, Diane E; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W; Loscalzo, Joseph; Joseph, Jacob

2012-12-01

Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. We examined the effects of selenium-deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium-supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arginase-1 deficiency.

PubMed

Sin, Yuan Yan; Baron, Garrett; Schulze, Andreas; Funk, Colin D

2015-12-01

Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. Gene transfer studies in these mice are revealing potential therapeutic options that can be exploited in the future. However, caution is advised in extrapolating results since the lethal disease phenotype in mice is much more severe than in humans indicating that the mouse models may not precisely recapitulate human disease etiology. Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. Lingering questions and future areas to be addressed relating to the clinical manifestations of ARG1 deficiency in liver and brain are also presented. Hopefully, this review will spark invigorated research efforts that lead to treatments with better clinical outcomes.

Veganism as a cause of iodine deficient hypothyroidism.

PubMed

Yeliosof, Olga; Silverman, Lawrence A

2018-01-26

Iodine deficiency is the most common cause of acquired hypothyroidism worldwide. Although uncommon in the Western world, the incidence of iodine deficiency may be rising due to the increased use of restrictive diets. We present a 23-month-old boy diagnosed with iodine deficiency hypothyroidism, induced by a vegan diet. This case highlights the risk for iodine deficiency in children on a vegan diet after discontinuation of breast/formula feeding that could lead to acquired hypothyroidism.

Micronutrient deficiencies in patients with chronic atrophic autoimmune gastritis: A review

PubMed Central

Cavalcoli, Federica; Zilli, Alessandra; Conte, Dario; Massironi, Sara

2017-01-01

Chronic atrophic autoimmune gastritis (CAAG) is an organ-specific autoimmune disease characterized by an immune response, which is directed towards the parietal cells and intrinsic factor of the gastric body and fundus and leads to hypochlorhydria, hypergastrinemia and inadequate production of the intrinsic factor. As a result, the stomach’s secretion of essential substances, such as hydrochloric acid and intrinsic factor, is reduced, leading to digestive impairments. The most common is vitamin B12 deficiency, which results in a megaloblastic anemia and iron malabsorption, leading to iron deficiency anemia. However, in the last years the deficiency of several other vitamins and micronutrients, such as vitamin C, vitamin D, folic acid and calcium, has been increasingly described in patients with CAAG. In addition the occurrence of multiple vitamin deficiencies may lead to severe hematological, neurological and skeletal manifestations in CAAG patients and highlights the importance of an integrated evaluation of these patients. Nevertheless, the nutritional deficiencies in CAAG are largely understudied. We have investigated the frequency and associated features of nutritional deficiencies in CAAG in order to focus on any deficit that may be clinically significant, but relatively easy to correct. This descriptive review updates and summarizes the literature on different nutrient deficiencies in CAAG in order to optimize the treatment and the follow-up of patients affected with CAAG. PMID:28216963

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

Proceedings of the 1993 Conference on Intelligent Computer-Aided Training and Virtual Environment Technology

NASA Technical Reports Server (NTRS)

Hyde, Patricia R.; Loftin, R. Bowen

1993-01-01

The volume 2 proceedings from the 1993 Conference on Intelligent Computer-Aided Training and Virtual Environment Technology are presented. Topics discussed include intelligent computer assisted training (ICAT) systems architectures, ICAT educational and medical applications, virtual environment (VE) training and assessment, human factors engineering and VE, ICAT theory and natural language processing, ICAT military applications, VE engineering applications, ICAT knowledge acquisition processes and applications, and ICAT aerospace applications.

G6PD Deficiency (Glucose-6-Phosphate Dehydrogenase) (For Parents)

MedlinePlus

... In rare cases, G6PD deficiency leads to chronic anemia . With the right precautions, a child with G6PD deficiency can lead a healthy and ... to rule out other possible causes of the anemia. If you feel that your child may be at risk because of either a ...

Glutathione synthetase deficiency: a family report.

PubMed Central

Pejaver, R K; Watson, A H

1994-01-01

Glutathione synthetase deficiency is a rare inborn error of metabolism. Low levels of and at times unstable molecules of glutathione synthetase leads to glutathione deficiency affecting various systems of the body. The inheritance is thought to be of autosomal recessive variety. We diagnosed the condition in a neonate and proceeded to investigate the family. The results are discussed below. PMID:8158601

Nuclear magnetic resonance metabolomics of iron deficiency in soybean leaves

USDA-ARS?s Scientific Manuscript database

Iron (Fe) deficiency is an important agricultural concern leading to lower yields and crop quality. A better understanding of the condition, at the metabolome level, could contribute to the design of strategies to ameliorate Fe deficiency problems. Fe-sufficient and Fe-deficient soybean leaf extract...

Adenosine deaminase deficiency: a review.

PubMed

Flinn, Aisling M; Gennery, Andrew R

2018-04-24

Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.

Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human

PubMed Central

Chang, Yi-Cheng; Yu, Yu-Hsiang; Shew, Jin-Yuh; Lee, Wei-Jei; Hwang, Juey-Jen; Chen, Yen-Hui; Chen, Yet-Ran; Wei, Pei-Chi; Chuang, Lee-Ming; Lee, Wen-Hwa

2013-01-01

Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a conserved oxidative stress sensor/transducer and deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this communication, we show that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx promoted preadipocytes to differentiate to adipocytes via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of CCAAT/enhancer-binding protein beta (C/EBPβ). This enhanced adipogenesis was alleviated by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms (SNPs) in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index (BMI) in several independent human populations. These results indicate that NPGPx protects against fat accumulation in mice and human via modulating ROS, and highlight the importance of targeting redox homeostasis in obesity management. Deficiency of the glutathione peroxidase NPGPx increases ROS levels in preadipocytes and promotes adipocyte differentiation via increasing oxidative stress and consequent increased fat mass and adipocyte hypertrophy. PMID:23828861

Nutrition and hair: deficiencies and supplements.

PubMed

Finner, Andreas M

2013-01-01

Hair follicle cells have a high turnover. A caloric deprivation or deficiency of several components, such as proteins, minerals, essential fatty acids, and vitamins, caused by inborn errors or reduced uptake, can lead to structural abnormalities, pigmentation changes, or hair loss, although exact data are often lacking. The diagnosis is established through a careful history, clinical examination of hair loss activity, and hair quality and confirmed through targeted laboratory tests. Examples of genetic hair disorders caused by reduced nutritional components are zinc deficiency in acrodermatitis enteropathica and copper deficiency in Menkes kinky hair syndrome. Copyright © 2013 Elsevier Inc. All rights reserved.

Partial thyrocyte-specific Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

PubMed

Patyra, Konrad; Jaeschke, Holger; Löf, Christoffer; Jännäri, Meeri; Ruohonen, Suvi T; Undeutsch, Henriette; Khalil, Moosa; Kero, Andreina; Poutanen, Matti; Toppari, Jorma; Chen, Min; Weinstein, Lee S; Paschke, Ralf; Kero, Jukka

2018-05-25

Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to its G protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the G s - and G q/11 -mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of G s -protein α subunit (Gα s ) in adult mice [tamoxifen-inducible G s protein α subunit deficient (iTGα s KO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGα s KO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGα s KO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGα s KO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gα s in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gα s deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gα s expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/G s /cAMP-mediated tumorigenesis.-Patyra, K., Jaeschke, H., Löf, C., Jännäri, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte-specific Gα s deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.

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…

Association between vitamin deficiency and metabolic disorders related to obesity.

PubMed

Thomas-Valdés, Samanta; Tostes, Maria das Graças V; Anunciação, Pamella C; da Silva, Bárbara P; Sant'Ana, Helena M Pinheiro

2017-10-13

Inappropriate food behavior contributes to obesity and leads to vitamin deficiency. This review discusses the nutritional status of water- and fat-soluble vitamins in obese subjects. We verified that most vitamins are deficient in obese individuals, especially the fat-soluble vitamins, folic acid, vitamin B 12 and vitamin C. However, some vitamins have been less evaluated in cases of obesity. The adipose tissue is considered a metabolic and endocrine organ, which in excess leads to changes in body homeostasis, as well as vitamin deficiency which can aggravate the pathological state. Therefore, the evaluation of vitamin status is of fundamental importance in obese individuals.

Genetics Home Reference: transcobalamin deficiency

MedlinePlus

... also have a shortage of white blood cells (neutropenia), which can lead to reduced immune system function. ... deficiency Seattle Children's Hospital: Anemia Seattle Children's Hospital: Neutropenia Washington University, St. Louis: Neuromuscular Disease Center: Vitamin ...

Zinc: physiology, deficiency, and parenteral nutrition.

PubMed

Livingstone, Callum

2015-06-01

The essential trace element zinc (Zn) has a large number of physiologic roles, in particular being required for growth and functioning of the immune system. Adaptive mechanisms enable the body to maintain normal total body Zn status over a wide range of intakes, but deficiency can occur because of reduced absorption or increased gastrointestinal losses. Deficiency impairs physiologic processes, leading to clinical consequences that include failure to thrive, skin rash, and impaired wound healing. Mild deficiency that is not clinically overt may still cause nonspecific consequences, such as susceptibility to infection and poor growth. The plasma Zn concentration has poor sensitivity and specificity as a test of deficiency. Consequently, diagnosis of deficiency requires a combination of clinical assessment and biochemical tests. Patients receiving parenteral nutrition (PN) are susceptible to Zn deficiency and its consequences. Nutrition support teams should have a strategy for assessing Zn status and optimizing this by appropriate supplementation. Nutrition guidelines recommend generous Zn provision from the start of PN. This review covers the physiology of Zn, the consequences of its deficiency, and the assessment of its status, before discussing its role in PN. © 2015 American Society for Parenteral and Enteral Nutrition.

Pyruvate dehydrogenase deficiency and epilepsy.

PubMed

Prasad, Chitra; Rupar, Tony; Prasad, Asuri N

2011-11-01

The pyruvate dehydrogenase complex (PDHc) is a mitochondrial matrix multienzyme complex that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the conversion of pyruvate into acetyl-CoA. PDHc deficiency is one of the commoner metabolic disorders of lactic acidosis presenting with neurological phenotypes that vary with age and gender. In this mini-review, we postulate mechanisms of epilepsy in the setting of PDHc deficiency using two illustrative cases (one with pyruvate dehydrogenase complex E1-alpha polypeptide (PDHA1) deficiency and the second one with pyruvate dehydrogenase complex E1-beta subunit (PDHB) deficiency (a rare subtype of PDHc deficiency)) and a selected review of published case series. PDHc plays a critical role in the pathway of carbohydrate metabolism and energy production. In severe deficiency states the resulting energy deficit impacts on brain development in utero resulting in structural brain anomalies and epilepsy. Milder deficiency states present with variable manifestations that include cognitive delay, ataxia, and seizures. Epileptogenesis in PDHc deficiency is linked to energy failure, development of structural brain anomalies and abnormal neurotransmitter metabolism. The use of the ketogenic diet bypasses the metabolic block, by providing a direct source of acetyl-CoA, leading to amelioration of some symptoms. Genetic counseling is essential as PDHA1 deficiency (commonest defect) is X-linked although females can be affected due to unfavorable lyonization, while PDHB and PDH phosphatase (PDP) deficiencies (much rarer defects) are of autosomal recessive inheritance. Research is in progress for looking into animal models to better understand pathogenesis and management of this challenging disorder. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Assessment of phantom dosimetry and image quality of i-CAT FLX cone-beam computed tomography.

PubMed

Ludlow, John B; Walker, Cameron

2013-12-01

The increasing use of cone-beam computed tomography in orthodontics has been coupled with heightened concern about the long-term risks of x-ray exposure in orthodontic populations. An industry response to this has been to offer low-exposure alternative scanning options in newer cone-beam computed tomography models. Effective doses resulting from various combinations of field of view size and field location comparing child and adult anthropomorphic phantoms with the recently introduced i-CAT FLX cone-beam computed tomography unit (Imaging Sciences, Hatfield, Pa) were measured with optical stimulated dosimetry using previously validated protocols. Scan protocols included high resolution (360° rotation, 600 image frames, 120 kV[p], 5 mA, 7.4 seconds), standard (360°, 300 frames, 120 kV[p], 5 mA, 3.7 seconds), QuickScan (180°, 160 frames, 120 kV[p], 5 mA, 2 seconds), and QuickScan+ (180°, 160 frames, 90 kV[p], 3 mA, 2 seconds). Contrast-to-noise ratio was calculated as a quantitative measure of image quality for the various exposure options using the QUART DVT phantom. Child phantom doses were on average 36% greater than adult phantom doses. QuickScan+ protocols resulted in significantly lower doses than standard protocols for the child (P = 0.0167) and adult (P = 0.0055) phantoms. The 13 × 16-cm cephalometric fields of view ranged from 11 to 85 μSv in the adult phantom and 18 to 120 μSv in the child phantom for the QuickScan+ and standard protocols, respectively. The contrast-to-noise ratio was reduced by approximately two thirds when comparing QuickScan+ with standard exposure parameters. QuickScan+ effective doses are comparable with conventional panoramic examinations. Significant dose reductions are accompanied by significant reductions in image quality. However, this trade-off might be acceptable for certain diagnostic tasks such as interim assessment of treatment results. Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc

Iron deficiency and iron deficiency anaemia in women.

PubMed

Percy, Laura; Mansour, Diana; Fraser, Ian

2017-04-01

Iron deficiency (ID) is the most common micronutrient deficiency worldwide with >20% of women experiencing it during their reproductive lives. Hepcidin, a peptide hormone mostly produced by the liver, controls the absorption and regulation of iron. Understanding iron metabolism is pivotal in the successful management of ID and iron deficiency anaemia (IDA) using oral preparations, parenteral iron or blood transfusion. Oral preparations vary in their iron content and can result in gastrointestinal side effects. Parenteral iron is indicated when there are compliance/tolerance issues with oral iron, comorbidities which may affect absorption or ongoing iron losses that exceed absorptive capacity. It may also be the preferred option when rapid iron repletion is required to prevent physiological decompensation or given preoperatively for non-deferrable surgery. As gynaecologists, we focus on managing women's heavy menstrual bleeding (HMB) and assume that primary care clinicians are treating the associated ID/IDA. We now need to take the lead in diagnosing, managing and initiating treatment for ID/IDA and treating HMB simultaneously. This dual management will significantly improve their quality of life. In this chapter we will summarise the importance of iron in cellular functioning, describe how to diagnose ID/IDA and help clinicians choose between the available treatment options. Copyright © 2016. Published by Elsevier Ltd.

Thiamin deficiency on fetal brain development with and without prenatal alcohol exposure.

PubMed

Kloss, Olena; Eskin, N A Michael; Suh, Miyoung

2018-04-01

Adequate thiamin levels are crucial for optimal health through maintenance of homeostasis and viability of metabolic enzymes, which require thiamine as a co-factor. Thiamin deficiency occurs during pregnancy when the dietary intake is inadequate or excessive alcohol is consumed. Thiamin deficiency leads to brain dysfunction because thiamin is involved in the synthesis of myelin and neurotransmitters (e.g., acetylcholine, γ-aminobutyric acid, glutamate), and its deficiency increases oxidative stress by decreasing the production of reducing agents. Thiamin deficiency also leads to neural membrane dysfunction, because thiamin is a structural component of mitochondrial and synaptosomal membranes. Similarly, in-utero exposure to alcohol leads to fetal brain dysfunction, resulting in negative effects such as fetal alcohol spectrum disorder (FASD). Thiamin deficiency and prenatal exposure to alcohol could act synergistically to produce negative effects on fetal development; however, this area of research is currently under-studied. This minireview summarizes the evidence for the potential role of thiamin deficiency in fetal brain development, with or without prenatal exposure to alcohol. Such evidence may influence the development of new nutritional strategies for preventing or mitigating the symptoms of FASD.

Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity.

PubMed

Morrow, Ryan M; Picard, Martin; Derbeneva, Olga; Leipzig, Jeremy; McManus, Meagan J; Gouspillou, Gilles; Barbat-Artigas, Sébastien; Dos Santos, Carlos; Hepple, Russell T; Murdock, Deborah G; Wallace, Douglas C

2017-03-07

Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease.

Manganese Deficiency Leads to Genotype-Specific Changes in Fluorescence Induction Kinetics and State Transitions1[C][OA

PubMed Central

Husted, Søren; Laursen, Kristian H.; Hebbern, Christopher A.; Schmidt, Sidsel B.; Pedas, Pai; Haldrup, Anna; Jensen, Poul E.

2009-01-01

Barley (Hordeum vulgare) genotypes display a marked difference in their ability to tolerate growth at low manganese (Mn) concentrations, a phenomenon designated as differential Mn efficiency. Induction of Mn deficiency in two genotypes differing in Mn efficiency led to a decline in the quantum yield efficiency for both, although faster in the Mn-inefficient genotype. Leaf tissue and thylakoid Mn concentrations were reduced under Mn deficiency, but no difference between genotypes was observed and no visual Mn deficiency symptoms were developed. Analysis of the fluorescence induction kinetics revealed that in addition to the usual O-J-I-P steps, clear K and D steps were developed in the Mn-inefficient genotype under Mn deficiency. These marked changes indicated damages to photosystem II (PSII). This was further substantiated by state transition measurements, indicating that the ability of plants to redistribute excitation energy was reduced. The percentage change in state transitions for control plants with normal Mn supply of both genotypes was 9% to 11%. However, in Mn-deficient leaves of the Mn-inefficient genotypes, state transitions were reduced to less than 1%, whereas no change was observed for the Mn-efficient genotypes. Immunoblotting and the chlorophyll a/b ratio confirmed that Mn deficiency in general resulted in a significant reduction in abundance of PSII reaction centers relative to the peripheral antenna. In addition, PSII appeared to be significantly more affected by Mn limitation than PSI. However, the striking genotypic differences observed in Mn-deficient plants, when analyzing state transitions and fluorescence induction kinetics, could not be correlated with specific changes in photosystem proteins. Thus, there is no simple linkage between protein expression and the differential reduction in state transition and fluorescence induction kinetics observed for the genotypes under Mn deficiency. PMID:19369593

A link between premenopausal iron deficiency and breast cancer malignancy

PubMed Central

2013-01-01

Background Young breast cancer (BC) patients less than 45 years old are at higher risk of dying from the disease when compared to their older counterparts. However, specific risk factors leading to this poorer outcome have not been identified. Methods One candidate is iron deficiency, as this is common in young women and a clinical feature of young age. In the present study, we used immuno-competent and immuno-deficient mouse xenograft models as well as hemoglobin as a marker of iron status in young BC patients to demonstrate whether host iron deficiency plays a pro-metastatic role. Results We showed that mice fed an iron-deficient diet had significantly higher tumor volumes and lung metastasis compared to those fed normal iron diets. Iron deficiency mainly altered Notch but not TGF-β and Wnt signaling in the primary tumor, leading to the activation of epithelial mesenchymal transition (EMT). This was revealed by increased expression of Snai1 and decreased expression of E-cadherin. Importantly, correcting iron deficiency by iron therapy reduced primary tumor volume, lung metastasis, and reversed EMT markers in mice. Furthermore, we found that mild iron deficiency was significantly associated with lymph node invasion in young BC patients (p<0.002). Conclusions Together, our finding indicates that host iron deficiency could be a contributor of poor prognosis in young BC patients. PMID:23800380

Immune deficiency in mouse models for inherited peripheral neuropathies leads to improved myelin maintenance.

PubMed

Schmid, C D; Stienekemeier, M; Oehen, S; Bootz, F; Zielasek, J; Gold, R; Toyka, K V; Schachner, M; Martini, R

2000-01-15

The adhesive cell surface molecule P(0) is the most abundant glycoprotein in peripheral nerve myelin and fulfills pivotal functions during myelin formation and maintenance. Mutations in the corresponding gene cause hereditary demyelinating neuropathies. In mice heterozygously deficient in P(0) (P(0)(+/-) mice), an established animal model for a subtype of hereditary neuropathies, T-lymphocytes are present in the demyelinating nerves. To monitor the possible involvement of the immune system in myelin pathology, we cross-bred P(0)(+/-) mice with null mutants for the recombination activating gene 1 (RAG-1) or with mice deficient in the T-cell receptor alpha-subunit. We found that in P(0)(+/-) mice myelin degeneration and impairment of nerve conduction properties is less severe when the immune system is deficient. Moreover, isolated T-lymphocytes from P(0)(+/-) mice show enhanced reactivity to myelin components of the peripheral nerve, such as P(0), P(2), and myelin basic protein. We hypothesize that autoreactive immune cells can significantly foster the demyelinating phenotype of mice with a primarily genetically based peripheral neuropathy.

Fetal and neonatal iron deficiency but not copper deficiency increases vascular complexity in the developing rat brain

PubMed Central

Bastian, Thomas W.; Santarriaga, Stephanie; Nguyen, Thu An; Prohaska, Joseph R.; Georgieff, Michael K.; Anderson, Grant W.

2015-01-01

Objectives Anemia caused by nutritional deficiencies, such as iron and copper deficiencies, is a global health problem. Iron and copper deficiencies have their most profound effect on the developing fetus/infant, leading to brain development deficits and poor cognitive outcomes. Tissue iron depletion or chronic anemia can induce cellular hypoxic signaling. In mice, chronic hypoxia induces a compensatory increase in brain blood vessel outgrowth. We hypothesized that developmental anemia, due to iron or copper deficiencies, induces angiogenesis/vasculogenesis in the neonatal brain. Methods To test our hypothesis, three independent experiments were performed where pregnant rats were fed iron- or copper-deficient diets from gestational day 2 through mid-lactation. Effects on the neonatal brain vasculature were determined using qPCR to assess mRNA levels of angiogenesis/vasculogenesis-associated genes and GLUT1 immunohistochemistry (IHC) to assess brain blood vessel density and complexity. Results Iron deficiency, but not copper deficiency, increased mRNA expression of brain endothelial cell- and angiogenesis/vasculogenesis-associated genes (i.e. Glut1, Vwf, Vegfa, Ang2, Cxcl12, and Flk1) in the neonatal brain, suggesting increased cerebrovascular density. Iron deficiency also increased hippocampal and cerebral cortical blood vessel branching by 62% and 78%, respectively. Discussion This study demonstrates increased blood vessel complexity in the neonatal iron-deficient brain, which is likely due to elevated angiogenic/vasculogenic signaling. At least initially, this is probably an adaptive response to maintain metabolic substrate homeostasis in the developing iron-deficient brain. However, this may also contribute to long-term neurodevelopmental deficits. PMID:26177275

Iodine deficiency disorders: contemporary scientific issues.

PubMed

Maberly, G F

1994-08-01

Iodine deficiency is the leading cause of preventable intellectual impairment and is associated with a spectrum of neurologic and developmental pathology. More than one billion people are at risk. The developing fetus, newborn, and young child are the most susceptible to the effects of an iodine-deficient diet. If intervention is not initiated in a timely fashion, the pathophysiologic abnormalities become resistant to treatment and permanent intellectual, neurologic, and somatic deficits result. The technology of iodine deficiency intervention is well established. Iodized salt, the preferred method, is easy to produce, administer in physiologic doses, and is cost effective. The distribution of iodized salt and social marketing are key to a successful iodine deficiency elimination program. In remote regions, iodized oil is a useful interim intervention. However, it is clear that technology is not enough. Any national effort to eliminate iodine deficiency must extend far beyond the Ministry of Health. The program will require the full participation of a range of national government ministries and agencies and the full support and participation of local or regional governments.

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Faslpr mice

PubMed Central

Xu, Zhiwei; Croker, Byron P.; Morel, Laurence

2013-01-01

The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment and for the induction of T-cell induced renal and skin pathology on a CD95 deficient (Faslpr)-background. We have previously shown that deficiency in cyclin-dependent kinase inhibitor p18INK4c (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting sub-loci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these sub-loci corresponds most likely to p18-deficiency. Another major locus mapping to a 2 Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to SLE disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell mediated organ damage. PMID:23698709

MeCP2 Deficiency Leads to Loss of Glial Kir4.1

PubMed Central

Cuddapah, Vishnu A.; Pacheco, Natasha L.; Holt, Leanne M.; Percy, Alan K.

2018-01-01

Abstract Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6–18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes carry out many essential functions required for normal brain functioning, including extracellular K+ buffering. Kir4.1, an inwardly rectifying K+ channel, is largely responsible for the channel-mediated K+ regulation by astrocytes. Loss-of-function mutations in Kir4.1 in human patients result in a severe neurodevelopmental disorder termed EAST or SESAME syndrome. Here, we evaluated astrocytic Kir4.1 expression in a murine model of Rett syndrome. We demonstrate by chromatin immunoprecipitation analysis that Kir4.1 is a direct molecular target of MeCP2. Astrocytes from Mecp2-deficient mice express significantly less Kir4.1 mRNA and protein, which translates into a >50% deficiency in Ba2+-sensitive Kir4.1-mediated currents, and impaired extracellular potassium dynamics. By examining astrocytes in isolation, we demonstrate that loss of Kir4.1 is cell autonomous. Assessment through postnatal development revealed that Kir4.1 expression in Mecp2-deficient animals never reaches adult, wild-type levels, consistent with a neurodevelopmental disorder. These are the first data implicating a direct MeCP2 molecular target in astrocytes and provide novel mechanistic insight explaining a potential mechanism by which astrocytic dysfunction may contribute to RTT. PMID:29464197

Evaluation of thromboelastography in two factor XII-deficient cats.

PubMed

Blois, Shauna L; Holowaychuk, Marie K; Wood, R Darren

2015-01-01

The current report describes thromboelastography (TEG) findings in two cats with factor XII (FXII) deficiency. The first cat was diagnosed with bilateral perinephric pseudocysts; hemostatic testing was performed prior to performing renal aspirates. The second cat was healthy; hemostatic testing was performed prior to inclusion into a research project. Both cats had markedly prolonged partial thromboplastin times and hypocoagulable TEG tracings when samples were activated with kaolin. However, when tissue factor (TF) was used to activate the sample, both cats had normal-to-hypercoagulable TEG tracings. The cats each had a subnormal FXII level. TEG is becoming widely used to investigate hemostasis in veterinary patients, and TEG results in cats with FXII deficiency have not been previously reported. FXII deficiency is the most common hereditary hemostatic defect in cats. While FXII deficiency does not lead to in vivo hemorrhagic tendencies, it can lead to marked prolongation in activated partial thromboplastin and activated clotting times, and cannot be differentiated from true hemorrhagic diatheses without measuring individual factor activity. With the increased use of TEG to evaluate hemostasis in veterinary patients, it is important to recognize the effects of FXII deficiency on this testing modality. The finding of a hypocoagulable kaolin-activated TEG tracing and a concurrent normal TF-activated TEG tracing in samples should prompt clinicians to consider ruling out FXII deficiency.

Evaluation of thromboelastography in two factor XII-deficient cats

PubMed Central

Holowaychuk, Marie K; Wood, R Darren

2015-01-01

Case summary The current report describes thromboelastography (TEG) findings in two cats with factor XII (FXII) deficiency. The first cat was diagnosed with bilateral perinephric pseudocysts; hemostatic testing was performed prior to performing renal aspirates. The second cat was healthy; hemostatic testing was performed prior to inclusion into a research project. Both cats had markedly prolonged partial thromboplastin times and hypocoagulable TEG tracings when samples were activated with kaolin. However, when tissue factor (TF) was used to activate the sample, both cats had normal-to-hypercoagulable TEG tracings. The cats each had a subnormal FXII level. Relevance and novel information TEG is becoming widely used to investigate hemostasis in veterinary patients, and TEG results in cats with FXII deficiency have not been previously reported. FXII deficiency is the most common hereditary hemostatic defect in cats. While FXII deficiency does not lead to in vivo hemorrhagic tendencies, it can lead to marked prolongation in activated partial thromboplastin and activated clotting times, and cannot be differentiated from true hemorrhagic diatheses without measuring individual factor activity. With the increased use of TEG to evaluate hemostasis in veterinary patients, it is important to recognize the effects of FXII deficiency on this testing modality. The finding of a hypocoagulable kaolin-activated TEG tracing and a concurrent normal TF-activated TEG tracing in samples should prompt clinicians to consider ruling out FXII deficiency. PMID:28491358

[Vitamin D-deficiency rickets: a case report from Burkina Faso].

PubMed

Sagna, Y; Ouédraogo, D-D; Dao, F; Diallo, O; Tiéno, H; Guira, O; Traoré, L O; Yanogo, A R D; Drabo, Y J

2013-01-01

Deficiency rickets results from a deficiency of vitamin D that is responsible for deficient calcium absorption, leading to failure of bone mineralization and cartilage bone growth, especially in children. We report the case of a 9-year-old girl who shows signs of rickets. Her family history, which includes similar malformations in several family members, led us to suggest vitamin D-resistant rickets, but all laboratory tests and response to treatment indicated deficiency rickets. Prophylaxis, at least for some very poor people, should be proposed for certain populations at risk, even in tropical zones.

Genetics Home Reference: triosephosphate isomerase deficiency

MedlinePlus

... more common in particular ethnic groups? Genetic Changes Mutations in the TPI1 gene cause triosephosphate isomerase deficiency . ... down to produce energy for cells. TPI1 gene mutations lead to the production of unstable enzymes or ...

[Distribution iodine deficiency diseases in coastal areas depending on geochemical conditions].

PubMed

Kiku, P F; Andryukov, B G

2014-01-01

In the Primorsky Krai there was performed a population ecological and hygienic analysis of the relationship between the content of chemical elements in the soil and thyroid morbidity in the population of the region. The assessment of the prevalence of iodine deficiency and iodine deficiency diseases was carried out on the basis of the impact of the priority environmental toxic (strontium, nickel, cadmium, lead, arsenic, tin) and essential (nickel, iron, germanium, molybdenum, zinc, selenium) trace elements on the level of iodine deficiency diseases. The level of thyroid pathology in the territory of Primorye was established to be the highest one in areas characterized by the severe iodine deficiency (Northwest geochemical zones), where the structure of thyroid diseases is presented mainly by diffuse nontoxic goiter. Thyroid diseases associated with iodine deficiency in the population of different age groups are the result of multiple and combined imbalance of trace elements, which causes a relative (secondary) iodine deficiency. Thyroid disease in Primorye are environmentally caused diseases of technogenic origin, they are a consequence of the relative iodine deficiency, when on the background of normal iodine supply an imbalance of zinc, iron, cobalt, manganese with excess of such toxic trace elements as lead, strontium, nickel and chromium takes place. Thyroid pathology associated with iodine deficiency, along with other environmentally dependent diseases can be considered as a marker of ecological environment trouble.

Effect of dietary calcium deficiency on the cardiac function of broiler chickens based on electro- and echocardiography.

PubMed

Zamani Moghaddam, Abdol Karim; Hassanpour, Hossein; Soroori, Sarang; Yadegari, Mehrdad; Tajeri, Ghodsieh

2010-06-01

To determine the effects of dietary calcium deficiency on the heart function of broiler chickens based on electro- and echocardiography, chicks were reared for 42 days and fed rations with different amounts of calcium. At 28 and 42 days of age, electrocardiographic and echocardiographic parameters were assessed. There were significant reductions of R wave amplitude (leads II and aVR) in the Ca-deficient group II at 42 day of age as compared to the control. S wave amplitudes were decreased in most leads but the decrease was significant (P < 0.05) only at 28 days (lead aVL, Ca-deficient group I) and 42 days (leads III, aVR, aVF, Ca-deficient groups I and II). T wave amplitudes were significantly (P < 0.05) decreased at 42 days (leads II, aVR and aVF) in the Ca-deficient group II compared to the control group. Variations in QT, ST and RR intervals were insignificant in the Ca-deficient groups compared with the control. There was a significant (P < 0.05) increase in left ventricular diameter at end-systole and a reduction of left ventricular fractional shortening in the Ca-deficient group II at 28 and 42 days as compared to the controls. Right ventricular fractional shortening was significantly (P < 0.05) decreased only in the Ca-deficient group II at 42 days of age. These results suggest that dose-dependent dietary calcium deficiency alters variations in electro- and echocardiographic parameters which could reflect decreased cardiac function in growing broiler chickens.

Rad GTPase Deficiency Leads to Cardiac Hypertrophy

PubMed Central

Tseng, Yu-Hua; Xie, Chang-Qing; Ilany, Jacob; Brüning, Jens C.; Sun, Zhongcui; Zhu, Xiaojun; Cui, Taixing; Youker, Keith A.; Yang, Qinglin; Day, Sharlene M.; Kahn, C. Ronald; Chen, Y. Eugene

2014-01-01

Background Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy. Methods and Results We document for the first time that levels of Rad mRNA and protein were decreased significantly in human failing hearts (n=10) compared with normal hearts (n=3; P<0.01). Similarly, Rad expression was decreased significantly in cardiac hypertrophy induced by pressure overload and in cultured cardiomyocytes with hypertrophy induced by 10 μmol/L phenylephrine. Gain and loss of Rad function in cardiomyocytes significantly inhibited and increased phenylephrine-induced hypertrophy, respectively. In addition, activation of calcium-calmodulin–dependent kinase II (CaMKII), a strong inducer of cardiac hypertrophy, was significantly inhibited by Rad overexpression. Conversely, downregulation of CaMKIIδ by RNA interference technology attenuated the phenylephrine-induced hypertrophic response in cardiomyocytes in which Rad was also knocked down. To further elucidate the potential role of Rad in vivo, we generated Rad-deficient mice and demonstrated that they were more susceptible to cardiac hypertrophy associated with increased CaMKII phosphorylation than wild-type littermate controls. Conclusions The present data document for the first time that Rad is a novel mediator that inhibits cardiac hypertrophy through the CaMKII pathway. The present study will have significant implications for understanding the mechanisms of cardiac hypertrophy and setting the basis for the development of new strategies for treatment of cardiac hypertrophy. PMID:18056528

Simulating Colour Vision Deficiency from a Spectral Image.

PubMed

Shrestha, Raju

2016-01-01

People with colour vision deficiency (CVD) have difficulty seeing full colour contrast and can miss some of the features in a scene. As a part of universal design, researcher have been working on how to modify and enhance the colour of images in order to make them see the scene with good contrast. For this, it is important to know how the original colour image is seen by different individuals with CVD. This paper proposes a methodology to simulate accurate colour deficient images from a spectral image using cone sensitivity of different cases of deficiency. As the method enables generation of accurate colour deficient image, the methodology is believed to help better understand the limitations of colour vision deficiency and that in turn leads to the design and development of more effective imaging technologies for better and wider accessibility in the context of universal design.

DNA Repair Deficiency in Neurodegeneration

PubMed Central

Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A.; Stevnsner, Tinna

2011-01-01

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration. PMID:21550379

Developing an Intelligent Computer-Aided Trainer

NASA Technical Reports Server (NTRS)

Hua, Grace

1990-01-01

The Payload-assist module Deploys/Intelligent Computer-Aided Training (PD/ICAT) system was developed as a prototype for intelligent tutoring systems with the intention of seeing PD/ICAT evolve and produce a general ICAT architecture and development environment that can be adapted by a wide variety of training tasks. The proposed architecture is composed of a user interface, a domain expert, a training session manager, a trainee model and a training scenario generator. The PD/ICAT prototype was developed in the LISP environment. Although it has been well received by its peers and users, it could not be delivered toe its end users for practical use because of specific hardware and software constraints. To facilitate delivery of PD/ICAT to its users and to prepare for a more widely accepted development and delivery environment for future ICAT applications, we have ported this training system to a UNIX workstation and adopted use of a conventional language, C, and a C-based rule-based language, CLIPS. A rapid conversion of the PD/ICAT expert system to CLIPS was possible because the knowledge was basically represented as a forward chaining rule base. The resulting CLIPS rule base has been tested successfully in other ICATs as well. Therefore, the porting effort has proven to be a positive step toward our ultimate goal of building a general purpose ICAT development environment.

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.

SIRT6 deficiency culminates in low-turnover osteopenia.

PubMed

Sugatani, Toshifumi; Agapova, Olga; Malluche, Hartmut H; Hruska, Keith A

2015-12-01

Deficiency of Sirtuin 6 (SIRT6), a chromatin-related deacetylase, in mice reveals severe premature aging phenotypes including osteopenia. However, the underlying molecular mechanisms of SIRT6 in bone metabolism are unknown. Here we show that SIRT6 deficiency in mice produces low-turnover osteopenia caused by impaired bone formation and bone resorption, which are mechanisms similar to those of age-related bone loss. Mechanistically, SIRT6 interacts with runt-related transcription factor 2 (Runx2) and osterix (Osx), which are the two key transcriptional regulators of osteoblastogenesis, and deacetylates histone H3 at Lysine 9 (H3K9) at their promoters. Hence, excessively elevated Runx2 and Osx in SIRT6(-/-) osteoblasts lead to impaired osteoblastogenesis. In addition, SIRT6 deficiency produces hyperacetylation of H3K9 in the promoter of dickkopf-related protein 1 (Dkk1), a potent negative regulator of osteoblastogenesis, and osteoprotegerin, an inhibitor of osteoclastogenesis. Therefore, the resulting up-regulation of Dkk1 and osteoprotegerin levels contribute to impaired bone remodeling, leading to osteopenia with a low bone turnover in SIRT6-deficient mice. These results establish a new link between SIRT6 and bone remodeling that positively regulates osteoblastogenesis and osteoclastogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetics Home Reference: adenosine deaminase 2 deficiency

MedlinePlus

... not fully understand how a loss of this enzyme's function leads to the features of ADA2 deficiency. They speculate that a lack of this enzyme may disrupt the balance between pro-inflammatory and ...

Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice

PubMed Central

Summer, R.; Little, F. F.; Ouchi, N.; Takemura, Y.; Aprahamian, T.; Dwyer, D.; Fitzsimmons, K.; Suki, B.; Parameswaran, H.; Fine, A.; Walsh, K.

2013-01-01

Adiponectin is an adipocyte-derived collectin that acts on a wide range of tissues including liver, brain, heart, and vascular endothelium. To date, little is known about the actions of adiponectin in the lung. Herein, we demonstrate that adiponectin is present in lung lining fluid and that adiponectin deficiency leads to increases in proinflammatory mediators and an emphysema-like phenotype in the mouse lung. Alveolar macrophages from adiponectin-deficient mice spontaneously display increased production of tumor necrosis factor-α (TNF-α) and matrix metalloproteinase (MMP-12) activity. Consistent with these observations, we found that pretreatment of alveolar macrophages with adiponectin leads to TNF-α and MMP-12 suppression. Together, our findings show that adiponectin leads to macrophage suppression in the lung and suggest that adiponectin-deficient states may contribute to the pathogenesis of inflammatory lung conditions such as emphysema. PMID:18326826

Fusion proteins comprising the catalytic domain of mutansucrase and a starch-binding domain can alter the morphology of amylose-free potato starch granules during biosynthesis.

PubMed

Nazarian Firouzabadi, Farhad; Kok-Jacon, Géraldine A; Vincken, Jean-Paul; Ji, Qin; Suurs, Luc C J M; Visser, Richard G F

2007-10-01

It has been shown previously that mutan can be co-synthesized with starch when a truncated mutansucrase (GtfICAT) is directed to potato tuber amyloplasts. The mutan seemed to adhere to the isolated starch granules, but it was not incorporated in the starch granules. In this study, GtfICAT was fused to the N- or C-terminus of a starch-binding domain (SBD). These constructs were introduced into two genetically different potato backgrounds (cv. Kardal and amf), in order to bring GtfICAT in more intimate contact with growing starch granules, and to facilitate the incorporation of mutan polymers in starch. Fusion proteins of the appropriate size were evidenced in starch granules, particularly in the amf background. The starches from the various GtfICAT/SBD transformants seemed to contain less mutan than those from transformants with GtfICAT alone, suggesting that the appended SBD might inhibit the activity of GtfICAT in the engineered fusion proteins. Scanning electron microscopy showed that expression of SBD-GtfICAT resulted in alterations of granule morphology in both genetic backgrounds. Surprisingly, the amf starches containing SBD-GtfICAT had a spongeous appearance, i.e., the granule surface contained many small holes and grooves, suggesting that this fusion protein can interfere with the lateral interactions of amylopectin sidechains. No differences in physico-chemical properties of the transgenic starches were observed. Our results show that expression of granule-bound and "soluble" GtfICAT can affect starch biosynthesis differently.

Applications of intelligent computer-aided training

NASA Technical Reports Server (NTRS)

Loftin, R. B.; Savely, Robert T.

1991-01-01

Intelligent computer-aided training (ICAT) systems simulate the behavior of an experienced instructor observing a trainee, responding to help requests, diagnosing and remedying trainee errors, and proposing challenging new training scenarios. This paper presents a generic ICAT architecture that supports the efficient development of ICAT systems for varied tasks. In addition, details of ICAT projects, built with this architecture, that deliver specific training for Space Shuttle crew members, ground support personnel, and flight controllers are presented. Concurrently with the creation of specific ICAT applications, a general-purpose software development environment for ICAT systems is being built. The widespread use of such systems for both ground-based and on-orbit training will serve to preserve task and training expertise, support the training of large numbers of personnel in a distributed manner, and ensure the uniformity and verifiability of training experiences.

Survey of Intelligent Computer-Aided Training

NASA Technical Reports Server (NTRS)

Loftin, R. B.; Savely, Robert T.

1992-01-01

Intelligent Computer-Aided Training (ICAT) systems integrate artificial intelligence and simulation technologies to deliver training for complex, procedural tasks in a distributed, workstation-based environment. Such systems embody both the knowledge of how to perform a task and how to train someone to perform that task. This paper briefly reviews the antecedents of ICAT systems and describes the approach to their creation developed at the NASA Lyndon B. Johnson Space Center. In addition to the general ICAT architecture, specific ICAT applications that have been or are currently under development are discussed. ICAT systems can offer effective solutions to a number of training problems of interest to the aerospace community.

HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.

PubMed

Khambu, Bilon; Huda, Nazmul; Chen, Xiaoyun; Antoine, Daniel J; Li, Yong; Dai, Guoli; Köhler, Ulrike A; Zong, Wei-Xing; Waguri, Satoshi; Werner, Sabine; Oury, Tim D; Dong, Zheng; Yin, Xiao-Ming

2018-06-01

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

Excessive fluoride consumption increases haematological alteration in subjects with iron deficiency, thalassaemia, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

PubMed

Pornprasert, Sakorn; Wanachantararak, Phenphichar; Kantawong, Fahsai; Chamnanprai, Supoj; Kongpan, Chatpat; Pienthai, Nattasit; Yanola, Jintana; Duangmano, Suwit; Prasannarong, Mujalin

2017-08-01

Excessive fluoride consumption leads to accelerated red blood cell death and anaemia. Whether that increases the haematological alteration in subjects with haematological disorders (iron deficiency, thalassaemia, and G-6-PD deficiency) is still unclear. The fluoride in serum and urine and haematological parameters of students at Mae Tuen School (fluoride endemic area) were analysed and compared to those of students at Baan Yang Poa and Baan Mai Schools (control areas). Iron deficiency, thalassaemia, and G-6-PD deficiency were also diagnosed in these students. The students at Mae Tuen School had significantly (P < 0.001) higher levels of mean fluoride in the serum and urine than those in control areas. In both control and fluoride endemic areas, students with haematological disorders had significantly lower levels of Hb, Hct, MCV, MCH, and MCHC than those without haematological disorders. Moreover, the lowest levels of Hb, MCH, and MCHC were observed in the students with haematological disorders who live in the fluoride endemic area. Thus, the excessive fluoride consumption increased haematological alteration in subjects with iron deficiency, thalassaemia, and G-6-PD deficiency and that may increase the risk of anaemia in these subjects.

Interleukin 1α-Deficient Mice Have an Altered Gut Microbiota Leading to Protection from Dextran Sodium Sulfate-Induced Colitis.

PubMed

Nunberg, Moran; Werbner, Nir; Neuman, Hadar; Bersudsky, Marina; Braiman, Alex; Ben-Shoshan, Moshe; Ben Izhak, Meirav; Louzoun, Yoram; Apte, Ron N; Voronov, Elena; Koren, Omry

2018-01-01

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders of the intestine, with as-yet-unclear etiologies, affecting over a million people in the United States alone. With the emergence of microbiome research, numerous studies have shown a connection between shifts in the gut microbiota composition (dysbiosis) and patterns of IBD development. In a previous study, we showed that interleukin 1α (IL-1α) deficiency in IL-1α knockout (KO) mice results in moderate dextran sodium sulfate (DSS)-induced colitis compared to that of wild-type (WT) mice, characterized by reduced inflammation and complete healing, as shown by parameters of weight loss, disease activity index (DAI) score, histology, and cytokine expression. In this study, we tested whether the protective effects of IL-1α deficiency on DSS-induced colitis correlate with changes in the gut microbiota and whether manipulation of the microbiota by cohousing can alter patterns of colon inflammation. We analyzed the gut microbiota composition in both control (WT) and IL-1α KO mice under steady-state homeostasis, during acute DSS-induced colitis, and after recovery using 16S rRNA next-generation sequencing. Additionally, we performed cohousing of both mouse groups and tested the effects on the microbiota and clinical outcomes. We demonstrate that host-derived IL-1α has a clear influence on gut microbiota composition, as well as on severity of DSS-induced acute colon inflammation. Cohousing both successfully changed the gut microbiota composition and increased the disease severity of IL-1α-deficient mice to levels similar to those of WT mice. This study shows a strong and novel correlation between IL-1α expression, microbiota composition, and clinical outcomes of DSS-induced colitis. IMPORTANCE Here, we show a connection between IL-1α expression, microbiota composition, and clinical outcomes of DSS-induced colitis. Specifically, we show that the mild colitis symptoms seen in IL-1α-deficient

Interleukin 1α-Deficient Mice Have an Altered Gut Microbiota Leading to Protection from Dextran Sodium Sulfate-Induced Colitis

PubMed Central

2018-01-01

α-deficient mice following administration of DSS are correlated with the unique gut microbiota compositions of the mice. However, when these mice are exposed to WT microbiota by cohousing, their gut microbiota composition returns to resemble that of WT mice, and their disease severity increases significantly. As inflammatory bowel diseases are such common diseases, with limited effective treatments to date, there is a great need to better understand the interactions between microbiota composition, the immune system, and colitis. This study shows correlation between microbiota composition and DSS resistance; it may potentially lead to the development of improved probiotics for IBD treatment. PMID:29766049

[Effect of carvedilol on T-type calcium current in myocytes of non-infarcted area of the rabbit healed myocardial infarction].

PubMed

Lin, Min; Zhu, Cai-Xing; Liu, Yan; Gao, Jin-Liao; Xu, Bin; Fu, Yi-Cheng; Lan, Yun-Feng; Li, Yang; Zhang, Jian-Cheng

2012-02-01

This article reports the investigation of the effect of carvedilol (Car) on T-type calcium current (I(Ca,T)) of noninfarcted ventricular myocytes in rabbit models of healed myocardial infarction (HMI). Rabbits with left anterior descending artery ligation were prepared and allowed to recover for 8 weeks, as HMI group. Animals undergoing an identical surgical procedure without coronary ligation were served as the sham-operated group (sham group). Whole cell voltage-clamp techniques were used to measure and compare currents in cells from the different groups. Noting that I(Ca,T) density in HMI cells increased markedly to -2.36 +/- 0.12 pA/pF (at -30 mV) compared with cells of sham, where little I(Ca,T) (-0.35 +/- 0.02 pA/pF) was observed. Meanwhile, further analysis revealed a significant hyperpolarizing shift of steady-state activation curve of I(Ca,T) in HMI cells, where the time constants of deactivation were prolonged and the time of recovery from inactivation was shortened. Finally, the amplitude of I(Ca,T) was increased. Carvedilol (1 micromol x L(-1)) was found to decrease the amplitude of I(Ca,T) to -1.38 +/- 0.07 pA/pF through inhibiting process of I(Ca,T) activation. Furthermore, carvedilol delayed recovery from inactivation of I(Ca,T) and shortened the time constants of deactivation in HMI cells. This study suggested that the application of carvedilol in HMI cells contributes to the dynamic changes in I(Ca,T) and may account for reduction of incidence of arrhythmia after myocardial infarction.

Iron Deficiency's Long-Term Effects: An Interview with Pediatrician Betsy Lozoff

ERIC Educational Resources Information Center

National Scientific Council on the Developing Child, 2006

2006-01-01

Betsy Lozoff is among the world's leading experts on iron deficiency and its effects on infant brain development and behavior. Iron deficiency is the most common single nutrient disorder in the world, affecting more than half of the world's infants and young children. Research by Lozoff and others has shown that there are long-lasting…

Late vitamin K deficiency bleeding leading to a diagnosis of cystic fibrosis: a case report.

PubMed

Ngo, B; Van Pelt, K; Labarque, V; Van De Casseye, W; Penders, J

2011-01-01

Vitamin K deficiency bleeding (VKDB) in infants still occurs despite worldwide use of prophylaxis. Clinical manifestations can be dramatic with over 50% of patients presenting with intracranial haemorrhage and a mortality rate of 20% in late vitamin K deficiency bleeding. Special attention should be given to infants with a high risk profile (preterm, breast feeding, cholestasis, malabsorption). A tentative diagnosis can be made observing quick normalisation of some easy-to-perform haemostatic parameters (PT, aPTT) after administration of vitamin K. Nowadays, VKDB can still be the first clinical sign of diseases causing malabsorption of fat-soluble vitamins. In this case report, VKDB led to the diagnosis of cystic fibrosis, the most common fatal autosomal recessive disease among Caucasian people.

XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice

PubMed Central

Yan, Catherine T.; Kaushal, Dhruv; Murphy, Michael; Zhang, Yu; Datta, Abhishek; Chen, Changzhong; Monroe, Brianna; Mostoslavsky, Gustavo; Coakley, Kristen; Gao, Yijie; Mills, Kevin D.; Fazeli, Alex P.; Tepsuporn, Suprawee; Hall, Giles; Mulligan, Richard; Fox, Edward; Bronson, Roderick; De Girolami, Umberto; Lee, Charles; Alt, Frederick W.

2006-01-01

Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations. PMID:16670198

Clusterin deficiency induces lipid accumulation and tissue damage in kidney.

PubMed

Heo, Jung-Yoon; Kim, Ji-Eun; Dan, Yongwook; Kim, Yong-Woon; Kim, Jong-Yeon; Cho, Kyu Hyang; Bae, Young Kyung; Im, Seung-Soon; Liu, Kwang-Hyeon; Song, In-Hwan; Kim, Jae-Ryong; Lee, In-Kyu; Park, So-Young

2018-05-01

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease. © 2018 Society for Endocrinology.

Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour.

PubMed

Winther, Gudrun; Pyndt Jørgensen, Betina M; Elfving, Betina; Nielsen, Denis Sandris; Kihl, Pernille; Lund, Sten; Sørensen, Dorte Bratbo; Wegener, Gregers

2015-06-01

Gut microbiota (GM) has previously been associated with alterations in rodent behaviour, and since the GM is affected by the diet, the composition of the diet may be an important factor contributing to behavioural changes. Interestingly, a magnesium restricted diet has been shown to induce anxiety and depressive-like behaviour in humans and rodents, and it could be suggested that magnesium deficiency may mediate the effects through an altered GM. The present study therefore fed C57BL/6 mice with a standard diet or a magnesium deficient diet (MgD) for 6 weeks, followed by behavioural testing in the forced swim test (FST) to evaluate depressive-like behaviour. An intraperitoneal glucose tolerance test (GTT) was performed 2 day after the FST to assess metabolic alterations. Neuroinflammatory markers were analysed from hippocampus. GM composition was analysed and correlated to the behaviour and hippocampal markers. It was found that mice exposed to MgD for 6 weeks were more immobile than control mice in the FST, suggesting an increased depressive-like behaviour. No significant difference was detected in the GTT. GM composition correlated positively with the behaviour of undisturbed C57BL/6 mice, feeding MgD diet altered the microbial composition. The altered GM correlated positively to the hippocampal interleukin-6. In conclusion, we hypothesise that imbalances of the microbiota-gut-brain axis induced by consuming a MgD diet, contributes to the development of depressive-like behaviour.

Properties of the low threshold Ca current in single frog atrial cardiomyocytes. A comparison with the high threshold Ca current

PubMed Central

1992-01-01

The properties of the low threshold Ca current (ICaT) in bullfrog (Rana catesbeiana) isolated atrial cardiomyocytes were studied using the whole-cell recording patch-clamp technique and compared with those of the high threshold Ca current (ICaL). In 91% of atrial cells we observed both ICaT and ICaL when collagenase and trypsin were used to dissociate the cells. But when pronase was used, only 30% of the cells exhibited ICaT. ICaT was never found in ventricular cells. ICaT could be investigated more easily when ICaL was inhibited by Cd ions (50 microM). Its kinetics were unchanged by substituting Ba for Ca, or in the presence of high concentrations of Ba. Both ICaT and ICaL exhibited reduced inactivation after high depolarizing prepulses. ICaT was found to be sensitive to dihydropyridines: 1 microM nifedipine decreased this current while 1 microM BAY K 8644 increased it; this occurred without significant variations in the steady-state inactivation curve. ICaT was more sensitive than ICaL to alpha 1-adrenergic and P2-purinergic stimulations, while ICaL was more sensitive to beta-adrenergic stimulation. Isoproterenol was still able to increase ICaT in the presence of high intracellular cAMP. Both currents were increased by 1 microM ouabain (although ICaL only transiently) and decreased by 10 microM ouabain. It is concluded that the two types of Ca channels can be observed in bullfrog atrial cells and that they are specifically altered by pharmacological agents and neuromediators. This may have implications for cardiac behavior. PMID:1279097

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency

PubMed Central

Hannibal, Luciana; Lysne, Vegard; Bjørke-Monsen, Anne-Lise; Behringer, Sidney; Grünert, Sarah C.; Spiekerkoetter, Ute; Jacobsen, Donald W.; Blom, Henk J.

2016-01-01

Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders. PMID:27446930

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.

PubMed

Hannibal, Luciana; Lysne, Vegard; Bjørke-Monsen, Anne-Lise; Behringer, Sidney; Grünert, Sarah C; Spiekerkoetter, Ute; Jacobsen, Donald W; Blom, Henk J

2016-01-01

Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.

Space shuttle orbiter leading-edge flight performance compared to design goals

NASA Technical Reports Server (NTRS)

Curry, D. M.; Johnson, D. W.; Kelly, R. E.

1983-01-01

Thermo-structural performance of the Space Shuttle orbiter Columbia's leading-edge structural subsystem for the first five (5) flights is compared with the design goals. Lessons learned from thse initial flights of the first reusable manned spacecraft are discussed in order to assess design maturity, deficiencies, and modifications required to rectify the design deficiencies. Flight data and post-flight inspections support the conclusion that the leading-edge structural subsystem hardware performance was outstanding for the initial five (5) flights.

Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice[S

PubMed Central

Solca, Curzio; Tint, G. Stephen; Patel, Shailendra B.

2013-01-01

The investigation of the human disease sitosterolemia (MIM 210250) has shed light not only on the pathways by which dietary sterols may traffic but also on how the mammalian body rids itself of cholesterol and defends against xenosterols. Two genes, ABCG5 and ABCG8, located at the sitosterolemia locus, each encodes a membrane-bound ABC half-transporter and constitutes a functional unit whose activity has now been shown to account for biliary and intestinal sterol excretion. Knockout mice deficient in Abcg5 or Abcg8 recapitulate many of the phenotypic features of sitosterolemia. During the course of our studies to characterize these knockout mice, we noted that these mice, raised on normal rodent chow, exhibited infertility as well as loss of abdominal fat. We show that, although sitosterolemia does not lead to any structural defects or to any overt endocrine defects, fertility could be restored if xenosterols are specifically blocked from entry and that the loss of fat is also reversed by a variety of maneuvers that limit xenosterol accumulation. These studies show that xenosterols may have a significant biological impact on normal mammalian physiology and that the Abcg5 or Abcg8 knockout mouse model may prove useful in investigating the role of xenosterols on mammalian physiology. PMID:23180829

Lethal Dysregulation of Energy Metabolism During Embryonic Vitamin E Deficiency

PubMed Central

McDougall, Melissa; Choi, Jaewoo; Kim, Hye-Kyeong; Bobe, Gerd; Stevens, J. Frederik; Cadenas, Enrique; Tanguay, Robert; Traber, Maret G.

2017-01-01

Vitamin E (α-tocopherol, VitE) was discovered in 1922 for its role in preventing embryonic mortality. We investigated the underlying mechanisms causing lethality using targeted metabolomics analyses of zebrafish VitE-deficient embryos over five days of development, which coincided with their increased morbidity and mortality. VitE deficiency resulted in peroxidation of docosahexaenoic acid (DHA), depleting DHA-containing phospholipids, especially phosphatidylcholine, which also caused choline depletion. This increased lipid peroxidation also increased NADPH oxidation, which depleted glucose by shunting it to the pentose phosphate pathway. VitE deficiency was associated with mitochondrial dysfunction with concomitant impairment of energy homeostasis. The observed morbidity and mortality outcomes could be attenuated, but not fully reversed, by glucose injection into VitE-deficient embryos at developmental day one. Thus, embryonic VitE deficiency in vertebrates leads to a metabolic reprogramming that adversely affects methyl donor status and cellular energy homeostasis with lethal outcomes. PMID:28095320

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

Autosomal Dominant Growth Hormone Deficiency (Type II).

PubMed

Alatzoglou, Kyriaki S; Kular, Dalvir; Dattani, Mehul T

2015-06-01

Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1. These mutations cause skipping of the third exon and lead to the production of a 17.5-kDa GH isoform that exerts a dominant negative effect on the secretion of the wild type GH. The identification of these mutations has clinical implications for the management of patients, as there is a well-documented correlation between the severity of the phenotype and the increased expression of the 17.5-kDa isoform. Patients with type II GHD have a variable height deficit and severity of GHD and may develop additional pituitary hormone defiencies over time, including ACTH, TSH and gonadotropin deficiencies. Therefore, their lifelong follow-up is recommended. Detailed studies on the effect of heterozygous GH1 mutations on the trafficking, secretion and action of growth hormone can elucidate their mechanism on a cellular level and may influence future treatment options for GHD type II.

Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

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

Kinoshita, Taisuke; Nagamatsu, Go, E-mail: gonag@sc.itc.keio.ac.jp; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012

2011-04-08

Highlights: {yields} iPS cells were induced with a fluorescence monitoring system. {yields} ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. {yields} iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. {yields} ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellularmore » response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.« less

Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management

PubMed Central

Comin‐Colet, Josep; de Francisco, Angel; Dignass, Axel; Doehner, Wolfram; S. P. Lam, Carolyn; Macdougall, Iain C.; Rogler, Gerhard; Camaschella, Clara; Kadir, Rezan; Kassebaum, Nicholas J.; Spahn, Donat R.; Taher, Ali T.; Musallam, Khaled M.

2017-01-01

Abstract Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease‐specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes. PMID:28612425

[Prolonged neuromuscular block in a patient with butyrylcholinesterase deficiency].

PubMed

Mabboux, I; Hary, B; Courcelle, S; Ceppa, F; Delacour, H

2016-05-01

Succinylcholine is a neuromuscular block whose duration of action depends on rapid hydrolysis by butyrylcholinesterase (BChE). In patients with common BChE activities, succinylcholine duration of action is short (10min). BChE deficiency induces a slower hydrolysis of the drug and consequently prolonged neuromuscular block, leading to apnea. We report a case of prolonged neuromuscular block after administration of succinylcholine in a 14-year-old boy. Biological investigations revealed a marked BChE deficiency (1099U/L) related to the presence of three point mutations in the BCHE gene in a compound heterozygous state: p.Asp70Gly (rs1799807), p.Ala539Tyr (rs1803274), and p.Phe118Valfs*12 (rs398124632). The diagnosis of genetic BChE deficiency (OMIM 177400) was retained. This case is intended to present the pathophysiology of genetic BChE deficiency, its management, and the diagnostic strategy to be implemented. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Nur77 deficiency leads to systemic inflammation in elderly mice.

PubMed

Li, Xiu-Ming; Lu, Xing-Xing; Xu, Qian; Wang, Jing-Ru; Zhang, Shen; Guo, Peng-Da; Li, Jian-Ming; Wu, Hua

2015-01-01

Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in the regulation of inflammation. However, the in vivo function of Nur77 remains largely unexplored. In the current study, we investigated the role of Nur77 in inflammation and immunity in mice. We found that elderly 8-month-old Nur77-deficient mice (Nur77(-/-)) developed systemic inflammation. Compared to wild-type (WT) mice (Nur77(+/+)), Nur77(-/-) mice showed splenomegaly, severe infiltration of inflammatory cells in several organs including liver, lung, spleen and kidney, increased hyperplasia of fibrous tissue in the lung and enlargement of kidney glomeruli. Additionally, Nur77(-/-) mice had increased production of pro-inflammatory cytokines and immunoglobulin, and elicited pro-inflammatory M1-like polarization in macrophages as revealed by increased expression of CXCL11 and INDO, and decreased expression of MRC1. These in vivo observations provide evidence for a pivotal role for Nur77 in the regulation of systemic inflammation and emphasize the pathogenic significance of Nur77 in vivo.

Cited1 Deficiency Suppresses Intestinal Tumorigenesis

PubMed Central

Young, Madeleine; Poetz, Oliver; Parry, Lee; Jenkins, John R.; Williams, Geraint T.; Dunwoodie, Sally L.; Watson, Alastair; Clarke, Alan R.

2013-01-01

Conditional deletion of Apc in the murine intestine alters crypt-villus architecture and function. This process is accompanied by multiple changes in gene expression, including upregulation of Cited1, whose role in colorectal carcinogenesis is unknown. Here we explore the relevance of Cited1 to intestinal tumorigenesis. We crossed Cited1 null mice with ApcMin/+ and AhCre+Apcfl/fl mice and determined the impact of Cited1 deficiency on tumour growth/initiation including tumour multiplicity, cell proliferation, apoptosis and the transcriptome. We show that Cited1 is up-regulated in both human and murine tumours, and that constitutive deficiency of Cited1 increases survival in ApcMin/+ mice from 230.5 to 515 days. However, paradoxically, Cited1 deficiency accentuated nearly all aspects of the immediate phenotype 4 days after conditional deletion of Apc, including an increase in cell death and enhanced perturbation of differentiation, including of the stem cell compartment. Transcriptome analysis revealed multiple pathway changes, including p53, PI3K and Wnt. The activation of Wnt through Cited1 deficiency correlated with increased transcription of β-catenin and increased levels of dephosphorylated β-catenin. Hence, immediately following deletion of Apc, Cited1 normally restrains the Wnt pathway at the level of β-catenin. Thus deficiency of Cited1 leads to hyper-activation of Wnt signaling and an exaggerated Wnt phenotype including elevated cell death. Cited1 deficiency decreases intestinal tumourigenesis in ApcMin/+ mice and impacts upon a number of oncogenic signaling pathways, including Wnt. This restraint imposed by Cited1 is consistent with a requirement for Cited1 to constrain Wnt activity to a level commensurate with optimal adenoma formation and maintenance, and provides one mechanism for tumour repression in the absence of Cited1. PMID:23935526

The Nature of Foot Ray Deficiency in Congenital Fibular Deficiency.

PubMed

Reyes, Bryan A; Birch, John G; Hootnick, David R; Cherkashin, Alex M; Samchukov, Mikhail L

Absent lateral osseous structures in congenital fibular deficiency, including the distal femur and fibula, have led some authors to refer to the nature of foot ray deficiency as "lateral" as well. Others have suggested that the ray deficiency is in the central portion of the midfoot and forefoot.We sought to determine whether cuboid preservation and/or cuneiform deficiency in the feet of patients with congenital fibular deficiency implied that the ray deficiency is central rather than lateral in patients with congenital fibular deficiency. We identified all patients with a clinical morphologic diagnosis of congenital fibular deficiency at our institution over a 15-year period. We reviewed the records and radiographs of patients who had radiographs of the feet to allow determination of the number of metatarsals, the presence or absence of a cuboid or calcaneocuboid fusion, the number of cuneiforms present (if possible), and any other osseous abnormalities of the foot. We excluded patients with 5-rayed feet, those who had not had radiographs of the feet, or whose radiographs were not adequate to allow accurate assessment of these radiographic features. We defined the characteristic "lateral (fifth) ray present" if there was a well-developed cuboid or calcaneocuboid coalition with which the lateral-most preserved metatarsal articulated. Twenty-six patients with 28 affected feet met radiographic criteria for inclusion in the study. All affected feet had a well-developed cuboid or calcaneocuboid coalition. The lateral-most ray of 25 patients with 26 affected feet articulated with the cuboid or calcaneocuboid coalition. One patient with bilateral fibular deficiency had bilateral partially deficient cuboids, and the lateral-most metatarsal articulated with the medial remnant of the deformed cuboids. Twenty-one of 28 feet with visible cuneiforms had 2 or 1 cuneiform. Although the embryology and pathogenesis of congenital fibular deficiency remain unknown, based on the

Treatment of plasminogen deficiency patients with fresh frozen plasma.

PubMed

Kızılocak, Hande; Ozdemir, Nihal; Dikme, Gürcan; Koç, Begüm; Atabek, Ayşe Ayzıt; Çokuğraş, Haluk; İskeleli, Güzin; Dönmez-Demir, Buket; Christiansen, Nina Merete; Ziegler, Maike; Ozdağ, Hilal; Schuster, Volker; Celkan, Tiraje

2018-02-01

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment. © 2017 Wiley Periodicals, Inc.

Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation

PubMed Central

Hasumi, Yukiko; Baba, Masaya; Hasumi, Hisashi; Huang, Ying; Lang, Martin; Reindorf, Rachel; Oh, Hyoung-bin; Sciarretta, Sebastiano; Nagashima, Kunio; Haines, Diana C.; Schneider, Michael D.; Adelstein, Robert S.; Schmidt, Laura S.; Sadoshima, Junichi; Marston Linehan, W.

2014-01-01

Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model. PMID:24908670

[Maternal vitamin B12 deficiency: cause for neurological symptoms in infancy].

PubMed

Lücke, T; Korenke, G C; Poggenburg, I; Bentele, K H P; Das, A M; Hartmann, H

2007-08-01

Symptoms of Vitamin B (12) deficiency in infancy include growth retardation, regression of psychomotor development, muscular hypotonia and brain atrophy. Besides an inappropriate vegetarian diet of the infants, a vegan diet or a pernicious anaemia of the mother may lead to an insufficient vitamin B (12) supply of the child. We report here the neurological symptoms of 4 fully breast-fed infants from mothers on vegan diet or with pernicious anaemia. Vitamin B (12) deficiency can easily be diagnosed by detection of methylmalonic acid when measuring the organic acids in urine. Vitamin B (12) deficiency should be avoided or diagnosed as early as possible since a supplementation of mother and child can prevent neurological symptoms of the baby. Furthermore, the neurological symptoms of the infant with manifest vitamin B (12) deficiency are (partially) reversible.

Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management.

PubMed

Cappellini, Maria Domenica; Comin-Colet, Josep; de Francisco, Angel; Dignass, Axel; Doehner, Wolfram; Lam, Carolyn S; Macdougall, Iain C; Rogler, Gerhard; Camaschella, Clara; Kadir, Rezan; Kassebaum, Nicholas J; Spahn, Donat R; Taher, Ali T; Musallam, Khaled M

2017-10-01

Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease-specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes. © 2017 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

Kinin B1 receptor deficiency leads to leptin hypersensitivity and resistance to obesity.

PubMed

Mori, Marcelo A; Araújo, Ronaldo C; Reis, Felipe C G; Sgai, Daniela G; Fonseca, Raphael G; Barros, Carlos C; Merino, Vanessa F; Passadore, Mariana; Barbosa, Ana M; Ferrari, Bernard; Carayon, Pierre; Castro, Charlles H M; Shimuta, Suma I; Luz, Jacqueline; Bascands, Jean-Loup; Schanstra, Joost P; Even, Patrick C; Oliveira, Suzana M; Bader, Michael; Pesquero, João B

2008-06-01

Kinins mediate pathophysiological processes related to hypertension, pain, and inflammation through the activation of two G-protein-coupled receptors, named B(1) and B(2). Although these peptides have been related to glucose homeostasis, their effects on energy balance are still unknown. Using genetic and pharmacological strategies to abrogate the kinin B(1) receptor in different animal models of obesity, here we present evidence of a novel role for kinins in the regulation of satiety and adiposity. Kinin B(1) receptor deficiency in mice (B(1)(-/-)) resulted in less fat content, hypoleptinemia, increased leptin sensitivity, and robust protection against high-fat diet-induced weight gain. Under high-fat diet, B(1)(-/-) also exhibited reduced food intake, improved lipid oxidation, and increased energy expenditure. Surprisingly, B(1) receptor deficiency was not able to decrease food intake and adiposity in obese mice lacking leptin (ob/ob-B(1)(-/-)). However, ob/ob-B(1)(-/-) mice were more responsive to the effects of exogenous leptin on body weight and food intake, suggesting that B(1) receptors may be dependent on leptin to display their metabolic roles. Finally, inhibition of weight gain and food intake by B(1) receptor ablation was pharmacologically confirmed by long-term administration of the kinin B(1) receptor antagonist SSR240612 to mice under high-fat diet. Our data suggest that kinin B(1) receptors participate in the regulation of the energy balance via a mechanism that could involve the modulation of leptin sensitivity.

GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice.

PubMed

Issop, Yasmin; Hathazi, Denisa; Khan, Muzamil Majid; Rudolf, Rüdiger; Weis, Joachim; Spendiff, Sally; Slater, Clarke R; Roos, Andreas; Lochmüller, Hanns

2018-06-14

Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and other genes downstream of this pathway cause congenital myasthenic syndrome (CMS) characterised by fatigable muscle weakness due to impaired neurotransmission. The precise pathomechanisms at the neuromuscular junction (NMJ) due to a deficiency in GFPT1 is yet to be discovered. One of the challenges we face is the viability of Gfpt1 -/- knockout mice. In this study, we use Cre/LoxP technology to generate a muscle-specific GFPT1 knockout mouse model, Gfpt1tm1d/tm1d, characteristic of the human CMS phenotype. Our data suggests a critical role for muscle derived GFPT1 in the development of the NMJ, neurotransmission, skeletal muscle integrity, and highlights that a deficiency in skeletal muscle alone is sufficient to cause morphological postsynaptic NMJ changes that are accompanied by presynaptic alterations despite the conservation of neuronal GFPT1 expression. In addition to the conventional morphological NMJ changes and fatigable muscle weakness, Gfpt1tm1d/tm1d mice display a progressive myopathic phenotype with the presence of tubular aggregates in muscle, characteristic of the GFPT1-CMS phenotype. We further identify an upregulation of skeletal muscle proteins glypican-1, farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha and Muscle-specific kinase which are known to be involved in the differentiation and maintenance of the NMJ. The Gfpt1tm1d/tm1d model allows for further investigation of pathophysiological consequences on genes and pathways downstream of GFPT1 likely to involve misglycosylation or hypoglycosylation of NMJs and muscle targets.

GABAB-ergic motor cortex dysfunction in SSADH deficiency

PubMed Central

Cohen, Leonardo G.; Pearl, Phillip L.; Fritsch, Brita; Jung, Nikolai H.; Dustin, Irene; Theodore, William H.

2012-01-01

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms. Methods: We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS). Results: Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups. Conclusions: Since long interval intracortical inhibition and cortical silent period are thought to reflect GABAB receptor–mediated inhibitory circuits, our results point to a particularly GABAB-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABAB receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABAB-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders. Neurology® 2012;79:47–54 PMID:22722631

Iodine Deficiency

MedlinePlus

... public health problem globally. Approximately 40% of the world’s population remains at risk for iodine deficiency. Iodine Deficiency ... common preventable cause of intellectual disabilities in the world. Even mild iodine ... deficiency is seen in an entire population, it is best managed by ensuring that common ...

Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis

PubMed Central

de Diego, Rebeca Pérez; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro; Puel, Anne; Plancoulaine, Sabine; Picard, Capucine; Herman, Melina; Cardon, Annabelle; Durandy, Anne; Bustamante, Jacinta; Vallabhapurapu, Sivakumar; Bravo, Jerónimo; Warnatz, Klaus; Chaix, Yves; Cascarrigny, Françoise; Lebon, Pierre; Rozenberg, Flore; Karin, Michael; Tardieu, Marc; Al-Muhsen, Saleh; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Abel, Laurent; Casanova, Jean-Laurent

2010-01-01

Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple receptors that induce interferon-α (IFN-α), IFN–β and IFN-λ production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here we reported the autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele was a loss-of-expression, loss-of-function, dominant-negative phenotype, and was associated with impaired, but not abolished TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency was associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3. Highlight sentence Autosomal dominant TRAF3 deficiency is a genetic etiology of herpes simplex encephalitis. Highlight sentence R118W TRAF3 allele is loss-of-function, loss-of-expression, and dominant-negative. Highlight sentence Human TRAF3 deficiency impairs the TLR3-dependent induction of anti-viral interferons. PMID:20832341

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

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

Sick sinus syndrome in HCN1-deficient mice.

PubMed

Fenske, Stefanie; Krause, Stefanie C; Hassan, Sami I H; Becirovic, Elvir; Auer, Franziska; Bernard, Rebekka; Kupatt, Christian; Lange, Philipp; Ziegler, Tilman; Wotjak, Carsten T; Zhang, Henggui; Hammelmann, Verena; Paparizos, Christos; Biel, Martin; Wahl-Schott, Christian A

2013-12-17

Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND. Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output. We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND.

Lead poisoning in children.

PubMed

Warniment, Crista; Tsang, Katrina; Galazka, Sim S

2010-03-15

The prevalence and severity of childhood lead poisoning have been greatly reduced since the removal of lead from paint and gasoline in the 1970s. Despite these efforts, approximately 310,000 U.S. children younger than five years have elevated blood lead levels. Health care professionals should perform targeted screening for lead poisoning in children who are Medicaid-enrolled or -eligible, foreign born, or identified as high risk by the Centers for Disease Control and Prevention (CDC) location-specific recommendations or by a personal risk questionnaire. Venous sampling is the preferred method for measuring blood lead levels, but a carefully collected finger-stick sample is an acceptable alternative. Capillary samples of elevated levels should be confirmed by a venous sample. The CDC recommends that the threshold for follow-up and intervention of lead poisoning be a blood lead level of 10 microg per dL or higher. Recommendations for treatment of elevated blood levels include a thorough environmental investigation, laboratory testing when appropriate, iron supplementation for iron-deficient children, and chelation therapy for blood lead levels of 45 microg per dL or more. Prevention consists of education and avoidance of lead-contaminated products.

Diagnosis of glutathione synthetase deficiency in newborn screening.

PubMed

Simon, E; Vogel, M; Fingerhut, R; Ristoff, E; Mayatepek, E; Spiekerkötter, U

2009-12-01

Glutathione synthetase (GSS) deficiency is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with haemolytic anaemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low GSS activity in erythrocytes or cultured skin fibroblasts. Diagnosis can be confirmed by mutational analysis. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. The most important determinants for outcome and survival in patients with GSS deficiency are early diagnosis and early initiation of treatment. The case of a newborn with GSS deficiency diagnosed by tandem mass spectrometry (MS/MS)-based newborn screening is described. After onset of clinical symptoms on the 2nd day of life, expanded newborn screening revealed normal results for all disorders included in the German screening programme; however, selective MS/MS screening revealed a >10-fold elevation of 5-oxoproline in dried blood, leading to the presumptive diagnosis of GSS deficiency by the 5th day of life. Diagnosis was later confirmed by detection of markedly reduced glutathione concentration in erythrocytes and mutational analysis of the GSS gene. Presently, GSS deficiency is not included in newborn screening programmes in Europe. As outcome depends significantly on early start of treatment, routine inclusion of this disorder in newborn screening panels should be considered.

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring.

PubMed

Kesby, James P; O'Loan, Jonathan C; Alexander, Suzanne; Deng, Chao; Huang, Xu-Feng; McGrath, John J; Eyles, Darryl W; Burne, Thomas H J

2012-04-01

Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Vitamin D deficiency: a new risk factor for type 2 diabetes?.

PubMed

Mezza, T; Muscogiuri, G; Sorice, G P; Prioletta, A; Salomone, E; Pontecorvi, A; Giaccari, A

2012-01-01

Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity. Copyright © 2012 S. Karger AG, Basel.

Nuclear magnetic resonance metabolomics of iron deficiency in soybean leaves.

PubMed

Lima, Marta R M; Diaz, Sílvia O; Lamego, Inês; Grusak, Michael A; Vasconcelos, Marta W; Gil, Ana M

2014-06-06

Iron (Fe) deficiency is an important agricultural concern that leads to lower yields and crop quality. A better understanding of the condition at the metabolome level could contribute to the design of strategies to ameliorate Fe-deficiency problems. Fe-sufficient and Fe-deficient soybean leaf extracts and whole leaves were analyzed by liquid (1)H nuclear magnetic resonance (NMR) and high-resolution magic-angle spinning NMR spectroscopy, respectively. Overall, 30 compounds were measurable and identifiable (comprising amino and organic acids, fatty acids, carbohydrates, alcohols, polyphenols, and others), along with 22 additional spin systems (still unassigned). Thus, metabolite differences between treatment conditions could be evaluated for different compound families simultaneously. Statistically relevant metabolite changes upon Fe deficiency included higher levels of alanine, asparagine/aspartate, threonine, valine, GABA, acetate, choline, ethanolamine, hypoxanthine, trigonelline, and polyphenols and lower levels of citrate, malate, ethanol, methanol, chlorogenate, and 3-methyl-2-oxovalerate. The data indicate that the main metabolic impacts of Fe deficiency in soybean include enhanced tricarboxylic acid cycle activity, enhanced activation of oxidative stress protection mechanisms and enhanced amino acid accumulation. Metabolites showing accumulation differences in Fe-starved but visually asymptomatic leaves could serve as biomarkers for early detection of Fe-deficiency stress.

Prevalence of glucose-6-phosphate dehydrogenase deficiency in jaundiced Egyptian neonates.

PubMed

M Abo El Fotoh, Wafaa Moustafa; Rizk, Mohammed Soliman

2016-12-01

The enzyme, Glucose-6-phosphate dehydrogenase (G6PD), deficiency leads to impaired production of reduced glutathione and predisposes the red cells to be damaged by oxidative metabolites, causing hemolysis. Deficient neonates may manifest clinically as hyperbilirubinemia or even kernicterus. This study was carried out to detect erythrocyte G6PD deficiency in neonatal hyperbilirubinemia. To determine the frequency and effect of G6PD deficiency, this study was conducted on 202 neonates with indirect hyperbilirubinemia. All term and preterm babies up to 13 day of age admitted with clinically evident jaundice were taken for the study. G6PD activity is measured by the UV-Kinetic Method using cellular enzyme determination reagents by spectrophotometry according to manufacturer's instructions. A total of 202 babies were enrolled in this study. Male babies outnumbered the female (71.3% versus 28.7%). Mean age of the study newborns was 3.75 ± 2.5 days. Eighteen neonates (8.9%) had G6PD deficiency, all are males. One case had combined G6PD deficiency and RH incompatibility. Mean serum total bilirubin was 17.2 ± 4.4 in G6PD deficient cases. There was significant positive correlation between the time of appearance of jaundice in days and G6PD levels in G6PD deficient cases. Neonatal hyperbilirubinemia is associated with various clinical comorbidities. G6PD deficiency is found to one important cause of neonatal jaundice developing on day 2 onwards.

Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease.

PubMed

Ahmad, Faraz; Singh, Kunal; Das, Debajyoti; Gowaikar, Ruturaj; Shaw, Eisha; Ramachandran, Arathy; Rupanagudi, Khader Valli; Kommaddi, Reddy Peera; Bennett, David A; Ravindranath, Vijayalakshmi

2017-12-01

Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer's disease (AD). Generation of reactive oxygen species (ROS) by β-amyloid has also been implicated in AD pathogenesis. However, it is unclear whether ROS contributes to synaptic dysfunction seen in AD pathogenesis and, therefore, we examined whether altered redox signaling could contribute to synaptic deficits in AD. Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old presymptomatic APP Swe /PS1ΔE9 (APP/PS1) mice, and this deficit was sustained till middle age (MA, 9-10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mechanistic target of rapamycin (mTOR) signaling, leading to deficiency in activity-dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from postmortem AD brains. Loss of activity-dependent protein translation occurs presymptomatically early in the pathogenesis of AD. This is caused by ROS-mediated loss of pAkt1, leading to reduced synaptic Akt1-mTOR signaling and is rescued by overexpression of Akt1. ROS-mediated damage is restricted to the synaptosomes, indicating selectivity. We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation that is essential for synaptic plasticity and maintenance. Therapeutic strategies promoting Akt1-mTOR signaling at synapses may provide novel target(s) for disease-modifying therapy in AD. Antioxid. Redox Signal. 27, 1269-1280.

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.

Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes.

PubMed

Tsuji, Ai; Nakamura, Toshinobu; Shibata, Katsumi

2015-01-01

Increased abnormal oocytes due to meiotic chromosome misalignment and spindle defects lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Here, we investigated the effect of biotin deficiency on oocyte quality. Three-week-old female ICR mice were fed a biotin-deficient or control diet (0, 0.004 g biotin/kg diet) for 21 days. On day 22, these mouse oocytes were analyzed by immunofluorescence. Due to biotin, undernutrition increased the frequency of abnormal oocytes (the biotin deficient vs. control: 40 vs. 16%). Next, the remaining mice in the biotin-deficient group were fed a control or biotin-deficient diet from day 22 to 42. Although biotin nutritional status in the recovery group was restored, the frequency of abnormal oocytes in the recovery group was still higher than that in the control group (48 vs. 18%). Our results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice.

Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency.

PubMed

Quinonez, Shane C; Seeley, Andrea H; Lam, Cindy; Glover, Thomas W; Barshop, Bruce A; Keegan, Catherine E

2017-01-01

Holocarboxylase synthetase (HLCS) deficiency is a rare autosomal recessive disorder that presents with multiple life-threatening metabolic derangements including metabolic acidosis, ketosis, and hyperammonemia. A majority of HLCS deficiency patients respond to biotin therapy; however, some patients show only a partial or no response to biotin therapy. Here, we report a neonatal presentation of HLCS deficiency with partial response to biotin therapy. Sequencing of HLCS showed a novel heterozygous mutation in exon 5, c.996G>C (p.Gln332His), which likely abolishes the normal intron 6 splice donor site. Cytogenetic analysis revealed that the defect of the other allele is a paracentric inversion on chromosome 21 that disrupts HLCS. This case illustrates that in addition to facilitating necessary family testing, a molecular diagnosis can optimize management by providing a better explanation of the enzyme's underlying defect. It also emphasizes the potential benefit of a karyotype in cases in which molecular genetic testing fails to provide an explanation.

Roles of chemical signals in regulation of the adaptive responses to iron deficiency.

PubMed

Liu, Xing Xing; He, Xiao Lin; Jin, Chong Wei

2016-05-03

Iron is an essential micronutrient for plants but is not readily accessible in most calcareous soils. Although the adaptive responses of plants to iron deficiency have been well documented, the signals involved in the regulatory cascade leading to their activation are not well understood to date. Recent studies revealed that chemical compounds, including sucrose, auxin, ethylene and nitric oxide, positively regulated the Fe-deficiency-induced Fe uptake processes in a cooperative manner. Nevertheless, cytokinins, jasmonate and abscisic acid were shown to act as negative signals in transmitting the iron deficiency information. The present mini review is to briefly address the roles of chemical signals in regulation of the adaptive responses to iron deficiency based on the literatures published in recent years.

A WRKY Transcription Factor Regulates Fe Translocation under Fe Deficiency.

PubMed

Yan, Jing Ying; Li, Chun Xiao; Sun, Li; Ren, Jiang Yuan; Li, Gui Xin; Ding, Zhong Jie; Zheng, Shao Jian

2016-07-01

Iron (Fe) deficiency affects plant growth and development, leading to reduction of crop yields and quality. Although the regulation of Fe uptake under Fe deficiency has been well studied in the past decade, the regulatory mechanism of Fe translocation inside the plants remains unknown. Here, we show that a WRKY transcription factor WRKY46 is involved in response to Fe deficiency. Lack of WRKY46 (wrky46-1 and wrky46-2 loss-of-function mutants) significantly affects Fe translocation from root to shoot and thus causes obvious chlorosis on the new leaves under Fe deficiency. Gene expression analysis reveals that expression of a nodulin-like gene (VACUOLAR IRON TRANSPORTER1-LIKE1 [VITL1]) is dramatically increased in wrky46-1 mutant. VITL1 expression is inhibited by Fe deficiency, while the expression of WRKY46 is induced in the root stele. Moreover, down-regulation of VITL1 expression can restore the chlorosis phenotype on wrky46-1 under Fe deficiency. Further yeast one-hybrid and chromatin immunoprecipitation experiments indicate that WRKY46 is capable of binding to the specific W-boxes present in the VITL1 promoter. In summary, our results demonstrate that WRKY46 plays an important role in the control of root-to-shoot Fe translocation under Fe deficiency condition via direct regulation of VITL1 transcript levels. © 2016 American Society of Plant Biologists. All Rights Reserved.

Comparison of the effects of divalent cations on the noradrenaline-evoked cation current in rabbit portal vein smooth muscle cells

PubMed Central

Aromolaran, A S; Large, W A

1999-01-01

The facilitatory effects of external Ca2+, Sr2+ and Ba2+ (Cao2+, Sro2+ and Bao2+) on the noradrenaline-evoked non-selective cation current (Icat) were compared in rabbit portal vein smooth muscle cells using patch pipette techniques. All divalent cations tested potentiated the amplitude of Icat and the potency sequence was Cao2+ > Sro2+ > Bao2+. Cao2+ and Sro2+ increased the amplitude of Icat by about eight times whereas Bao2+ produced only a threefold facilitation. The current-voltage relationship of Icat was not changed by Cao2+, Sro2+ or Bao2+. From noise analysis the single channel conductance (γ) was approximately 10 pS in divalent cation-free solution but was about 20 pS with Cao2+, Sro2+ and Bao2+. From noise and voltage-jump experiments it was apparent that at least three kinetically resolvable channel states are associated with Icat in divalent cation-free solution. Cao2+ and Sro2+ produced marked changes in the characteristics of the power spectrum and relaxations of Icat in response to voltage steps, consistent with a shift in the equilibrium between the channel states, whereas Bao2+ produced minimal effects. The data show that Cao2+, Sro2+ and Bao2+ increase the amplitude of Icat, which results in part from an increase in the single channel conductance. In addition the results suggest that Cao2+ and Sro2+ alter the kinetic behaviour of the single channels whereas Bao2+ has little effect on the equilibrium between the channel states. PMID:10545143

Vitamin Deficiency Anemia

MedlinePlus

... are unique to specific vitamin deficiencies. Folate-deficiency anemia risk factors include: Undergoing hemodialysis for kidney failure. ... the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack of intrinsic factor. Most ...

Early-Life Persistent Vitamin D Deficiency Alters Cardiopulmonary Responses to Particulate Matter-Enhanced Atmospheric Smog in Adult Mice

EPA Science Inventory

This study demonstrates that early-life persistent vitamin D deficiency alters the cardiopulmonary response to smog in mice and may increase risk of adverse effects. Early life nutritional deficiencies can lead to increased cardiovascular susceptibility to environme...

Isoleucine Deficiency in a Neonate Treated for Maple Syrup Urine Disease Masquerading as Acrodermatitis Enteropathica.

PubMed

Ross, Benjamin; Kumar, Manish; Srinivasan, Hema; Ekbote, Alka V

2016-08-08

Special diet with restricted branched-chain-amino-acids used for treating maple syrup urine disease can lead to specific amino acid deficiencies. We report a neonate who developed skin lesions due to isoleucine deficiency while using specialised formula. Feeds were supplemented with expressed breast milk. This caused biochemical and clinical improvement with resolution of skin lesions. Breast milk is a valuable and necessary adjunct to specialized formula in maple syrup urine disease to prevent specific amino acid deficiency in the neonatal period.

What Are Rare Clotting Factor Deficiencies?

MedlinePlus

... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

Impaired copper and iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy.

PubMed

Spinazzi, Marco; Sghirlanzoni, Angelo; Salviati, Leonardo; Angelini, Corrado

2014-12-01

Severe copper deficiency leads in humans to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated. We tested whether copper deficit leads to alterations in fundamental copper-dependent proteins and in iron metabolism in blood and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance. We evaluated the expression of critical copper enzymes, of iron-related proteins, and copper chaperones and transporters in blood and muscles from five copper-deficient patients presenting with subacute sensory ataxia, muscle paralysis, liver steatosis and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases. The antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper-deficient patients compared with controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the haem-proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, was strikingly increased, while antioxidant protein 1 was diminished. copper-dependent enzymes with critical functions in antioxidant defences, in mitochondrial energy production, and in iron metabolism are affected in blood and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention. © 2013 British Neuropathological Society.

CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders.

PubMed

Hirano, Michio; Garone, Caterina; Quinzii, Catarina M

2012-05-01

Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Here, we describe clinical and molecular features of CoQ(10) deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ(10) deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ(10) biosynthesis, often improve with CoQ(10) supplementation. In vitro and in vivo studies of CoQ(10) deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ(10) deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. CoQ(10) deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. Studies of CoQ(10) deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010. Copyright © 2012 Elsevier B.V. All rights reserved.

Genetic basis of human complement C8[beta] deficiency

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

Kaufmann, T.; Rittner, C.; Schneider, P.M.

1993-06-01

The eighth component of human complement (c8) is a serum protein consisting of three chains ([alpha], [beta], and [gamma]) and encoded by three different genes, C8A, C8B, and C8G. C8A and C8B are closely linked on chromosome 1p, whereas C8G is located on chromosome 9q. In the serum the [beta] subunit is non-covalently bound to the disulfide-linked [alpha]-[gamma] subunit. Patients with C8[beta] deficiency suffer from recurrent neisserial infections such as meningitis. Exon-specific polymerase chain reaction (PCR) amplification with primer pairs from the flanking intron sequences was used to amplify all 12 C8B exons separately. No difference regarding the exon sizesmore » was observed in a C8[beta]-deficient patient compared with a normal person. Therefore, direct sequence analysis of all exon-specific PCR products from normal and C8[beta]-deficient individuals was carried out. As a cause for C8[beta] deficiency, we found a single C-T exchange in exon 9 leading to a stop codon. An allele-specific PCR system was designed to detect the normal and the deficiency allele simultaneously. Using this approach as well as PCR typing of the Taql polymorphism located in intron 11, five families with 7 C8[beta]-deficient members were investigated. The mutation was not found to be restricted to one of the two Taql RFLP alleles. The mutant allele was observed in all families investigated and can therefore be regarded as a major cause of C8[beta] deficiency in the Caucasian population. In addition, two C8[beta]-deficient patients were found to be heterozygous for the C-T exchange. The molecular basis of the alleles without this point mutation also causing deficiency has not yet been defined. 23 refs., 4 figs., 3 tabs.« less

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.

Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease

PubMed Central

Ahmad, Faraz; Singh, Kunal; Das, Debajyoti; Gowaikar, Ruturaj; Shaw, Eisha; Ramachandran, Arathy; Rupanagudi, Khader Valli; Kommaddi, Reddy Peera; Bennett, David A.

2017-01-01

Abstract Aims: Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer's disease (AD). Generation of reactive oxygen species (ROS) by β-amyloid has also been implicated in AD pathogenesis. However, it is unclear whether ROS contributes to synaptic dysfunction seen in AD pathogenesis and, therefore, we examined whether altered redox signaling could contribute to synaptic deficits in AD. Results: Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old presymptomatic APPSwe/PS1ΔE9 (APP/PS1) mice, and this deficit was sustained till middle age (MA, 9–10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mechanistic target of rapamycin (mTOR) signaling, leading to deficiency in activity-dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from postmortem AD brains. Innovation: Loss of activity-dependent protein translation occurs presymptomatically early in the pathogenesis of AD. This is caused by ROS-mediated loss of pAkt1, leading to reduced synaptic Akt1-mTOR signaling and is rescued by overexpression of Akt1. ROS-mediated damage is restricted to the synaptosomes, indicating selectivity. Conclusions: We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation that is essential for synaptic plasticity and maintenance. Therapeutic strategies promoting Akt1-mTOR signaling at synapses may provide novel target(s) for disease-modifying therapy in AD. Antioxid. Redox Signal. 27, 1269–1280. PMID:28264587

Cardiovascular and intestinal responses to oxidative and nitrosative stress during prolonged magnesium deficiency.

PubMed

Weglicki, William B; Chmielinska, Joanna J; Kramer, Jay H; Mak, I Tong

2011-08-01

In rodents with dietary magnesium deficiency (Mg deficiency), hypomagnesemia, occurs leading to a rise in circulating substance P from neuronal tissues to trigger systemic inflammatory stress in cardiac and intestinal tissues. Sustained elevations of substance P may result from impaired neutral endopeptidase (NEP) activity due to reactive oxygen and reactive nitrogen species. Associated increase in intestinal permeability includes infiltration of WBC and endotoxemia, which can further amplify the systemic inflammatory response that leads to impaired contractile function associated with up-regulation of the cardiac CD14 endotoxin receptor. The neurogenic signal transduction pathways that we have identified in the pro-oxidant/pro-inflammatory processes found with prolonged hypomagnesemia are described in this report.

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

PubMed

Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas D E; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

2017-03-01

Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid. © The Author 2017. Published by Oxford University Press.

Uterine Dysfunction in Biglycan and Decorin Deficient Mice Leads to Dystocia during Parturition

PubMed Central

Wu, Zhiping; Aron, Abraham W.; Macksoud, Elyse E.; Iozzo, Renato V.; Hai, Chi-Ming; Lechner, Beatrice E.

2012-01-01

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild-type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction. PMID:22253749

Colour vision deficiency.

PubMed

Simunovic, M P

2010-05-01

Colour vision deficiency is one of the commonest disorders of vision and can be divided into congenital and acquired forms. Congenital colour vision deficiency affects as many as 8% of males and 0.5% of females--the difference in prevalence reflects the fact that the commonest forms of congenital colour vision deficiency are inherited in an X-linked recessive manner. Until relatively recently, our understanding of the pathophysiological basis of colour vision deficiency largely rested on behavioural data; however, modern molecular genetic techniques have helped to elucidate its mechanisms. The current management of congenital colour vision deficiency lies chiefly in appropriate counselling (including career counselling). Although visual aids may be of benefit to those with colour vision deficiency when performing certain tasks, the evidence suggests that they do not enable wearers to obtain normal colour discrimination. In the future, gene therapy remains a possibility, with animal models demonstrating amelioration following treatment.

Iron deficiency anemia due to excessive green tea drinking.

PubMed

Fan, Frank S

2016-11-01

Tea interferes with iron absorption and can lead to iron deficiency anemia when consumed in large quantities. The rechallenge effect of green tea on anemia in a middle-aged man emphasizes the potential causal role of this beverage. Lifestyle and dietary habits are important diagnostic considerations in diseases of this type.

Nitric oxide ameliorates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

PubMed

Kaushik, Manish Singh; Srivastava, Meenakshi; Srivastava, Alka; Singh, Anumeha; Mishra, Arun Kumar

2016-11-01

In cyanobacterium Anabaena 7120, iron deficiency leads to oxidative stress with unavoidable consequences. Nitric oxide reduces pigment damage and supported the growth of Anabaena 7120 in iron-deficient conditions. Elevation in nitric oxide accumulation and reduced superoxide radical production justified the role of nitric oxide in alleviating oxidative stress in iron deficiency. Increased activities of antioxidative enzymes and higher levels of ROS scavengers (ascorbate, glutathione and thiol) in iron deficiency were also observed in the presence of nitric oxide. Nitric oxide also supported the membrane integrity of Anabaena cells and reduces protein and DNA damage caused by oxidative stress induced by iron deficiency. Results suggested that nitric oxide alleviates the damaging effects of oxidative stress induced by iron deficiency in cyanobacterium Anabaena 7120.

[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.

Catalase deficiency may complicate urate oxidase (rasburicase) therapy.

PubMed

Góth, László; Bigler, N William

2007-09-01

Patients with low (inherited and acquired) catalase activities who are treated with infusion of uric acid oxidase because they are at risk of tumour lysis syndrome may experience very high concentrations of hydrogen peroxide. They may suffer from methemoglobinaemia and haemolytic anaemia which may be attributed either to deficiency of glucose-6-phosphate dehydrogenase or to other unknown circumstances. Data have not been reported from catalase deficient patients who were treated with uric acid oxidase. It may be hypothesized that their decreased blood catalase could lead to the increased concentration of hydrogen peroxide which may cause haemolysis and formation of methemoglobin. Blood catalase activity should be measured for patients at risk of tumour lysis syndrome prior to uric acid oxidase treatment.

Vitamin B12 deficiency: unusual cause of jaundice in an adolescent.

PubMed

Katakam, Phalguna Kousika; Hegde, Asha P; Venkataramaiahyappa, Manju

2018-01-12

Vitamin B 12 deficiency in vegans is a known cause of megaloblastic anaemia. We report an adolescent girl who presented with jaundice and weight loss for 6 months secondary to vitamin B 12 deficiency, leading to megaloblastic anaemia. Replacement with vitamin B 12 reversed her symptoms, resulting in weight gain, and normalised her haemoglobin, red blood cell morphology, bilirubin levels and serum vitamin B 12 levels. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Two soybean bHLH factors regulate response to iron deficiency.

PubMed

Li, Lin; Gao, Wenwen; Peng, Qi; Zhou, Bin; Kong, Qihui; Ying, Yinghui; Shou, Huixia

2018-03-25

Iron is an indispensable micronutrient for plant growth and development. Limited bioavailability of Fe in the soil leads to iron deficiency chlorosis in plants and yield loss. In this study, two soybean basic helix-loop-helix transcription factors, GmbHLH57 and GmbHLH300, were identified in response to Fe-deficiency. Both transcription factors are expressed in roots and nodules, and are induced by Fe deficiency; these patterns were confirmed in transgenic hairy roots expressing constructs of the endogenous promoters fused to a GUS reporter gene. Bimolecular fluorescence complementation, yeast two-hybrid and coimmunoprecipitation (co-IP) assays indicated a physical interaction between GmbHLH57 and GmbHLH300. Studies on transgenic soybeans overexpressing GmbHLH57 and GmbHLH300 revealed that overexpression of each transcription factor, alone, results in no change of the responses to Fe deficiency, whereas overexpression of both transcription factors upregulated the downstream Fe uptake genes and increased the Fe content in these transgenic plants. Compared to wild type, these double overexpression transgenic plants were more tolerant to Fe deficiency. Taken together, our findings establish that GmbHLH57 and GmbHLH300 are important transcription factors involved in Fe homeostasis in soybean. © 2018 Institute of Botany, Chinese Academy of Sciences.

Effects of lead exposure before pregnancy and dietary calcium during pregnancy on fetal development and lead accumulation.

PubMed Central

Han, S; Pfizenmaier, D H; Garcia, E; Eguez, M L; Ling, M; Kemp, F W; Bogden, J D

2000-01-01

Millions of women of child-bearing age have substantial bone lead stores due to lead exposure as children. Dietary calcium ingested simultaneously with lead exposure can reduce lead absorption and accumulation. However, the effects of dietary calcium on previously accumulated maternal lead stores and transfer to the fetus have not been investigated. We studied the effects of lead exposure of female rats at an early age on fetal development during a subsequent pregnancy. We gave 5-week-old female Sprague-Dawley rats lead as the acetate in their drinking water for 5 weeks; controls received equimolar sodium acetate. This was followed by a 1-month period without lead exposure before mating. We randomly assigned pregnant rats (n = 39) to diets with a deficient (0.1%) or normal (0.5%) calcium content during pregnancy. A total of 345 pups were delivered alive. Lead-exposed dams and their pups had significantly higher blood lead concentrations than controls, but the concentrations were in the range of those found in many pregnant women. Pups born to dams fed the calcium-deficient diet during pregnancy had higher blood and organ lead concentrations than pups born to dams fed the 0. 5% calcium diet. Pups born to lead-exposed dams had significantly (p<0.0001) lower mean birth weights and birth lengths than controls. There were significant inverse univariate associations between dam or pup organ lead concentrations and birth weight or length. The 0.5% calcium diet did not increase in utero growth. Stepwise regression analysis demonstrated that greater litter size and female sex were significantly associated with reduced pup birth weight and length. However, lead exposure that ended well before pregnancy was significantly (p<0.0001) associated with reduced birth weight and length, even after litter size, pup sex, and dam weight gain during pregnancy were included in the regression analysis. The data demonstrate that an increase in dietary calcium during pregnancy can reduce

Zinc induces long-term upregulation of T-type calcium current in hippocampal neurons in vivo.

PubMed

Ekstein, Dana; Benninger, Felix; Daninos, Moshe; Pitsch, Julika; van Loo, Karen M J; Becker, Albert J; Yaari, Yoel

2012-11-15

Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T-type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation. We tested this hypothesis by monitoring for 18 days the effects of zinc and ibotenic acid (a neurotoxic agent serving as control for zinc), injected into the right lateral ventricle, on I(CaT) in rat CA1 pyramidal cells. Both zinc and ibotenic acid caused marked hippocampal lesions on the side of injection, but only minor damage to contralateral hippocampi. Zinc, but not ibotenic acid, caused upregulation of a nickel-sensitive I(CaT) in a subset of contralateral CA1 pyramidal cells, appearing 2 days after injection and lasting for about 2 weeks thereafter. In contrast, acute application of zinc to CA1 pyramidal cells promptly blocked I(CaT). These data indicate that extracellular zinc has a dual effect on I(CaT), blocking it acutely while causing its long-term upregulation. Through the latter effect, zinc may regulate the intrinsic excitability of principal neurons, particularly in pathological conditions associated with enhanced release of zinc, such as SE.

Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency.

PubMed

Belfield, Kristen D; Tichy, Eric M

2018-02-01

The pathophysiology, diagnosis, and medication-use implications of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzyme deficiency in humans, are reviewed. Originally identified as favism in patients who experienced hemolysis after ingestion of fava beans, G6PD deficiency results from an X-linked chromosomal mutation that leads to reduced activity of the enzyme responsible for the final step of the pentose phosphate pathway, through which reduced nicotinamide adenine dinucleotide phosphate required for protection of cells from oxidative stress is produced. G6PD deficiency affects about 400 million people worldwide. Diagnosis of G6PD can be made through detection of enzymatic activity (by spectrophotometric testing, fluorescence testing, or formazan-based spot testing) or molecular analysis to detect known mutations of the gene encoding G6PD. Most individuals with G6PD deficiency are asymptomatic throughout life. Symptoms of acute hemolysis associated with G6PD deficiency include anemia, fatigue, back or abdominal pain, jaundice, and hemoglobinuria. The most common precipitators of oxidative stress and hemolysis in G6PD deficiency include medication use and infection. G6PD deficiency should be considered in patients who experience acute hemolysis after exposure to known oxidative medications, infection, or ingestion of fava beans. A diagnosis of G6PD deficiency is most often made through enzymatic activity detection, but molecular analysis may be required in females heterozygous for the disorder. When clinically feasible, rasburicase, primaquine, dapsone, pegloticase, and methylene blue should not be used until a G6PD diagnostic test has been performed. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Taurine and taurine-deficiency in the perinatal period.

PubMed

Aerts, Leona; Van Assche, Frans André

2002-01-01

Taurine, a non-protein sulfur amino-acid, is the most abundant free amino-acid in the body and plays an important role in several essential biological processes. Apart from its role in cholesterol degradation, it acts as neurotransmitter, and has a function as osmoregulator and antioxidant in most body tissues. During pregnancy, taurine accumulates in the maternal tissues, to be released in the perinatal period to the fetus via the placenta and to the newborn via the maternal milk. It is accumulated especially in the fetal and neonatal brain. Low maternal taurine levels result in low fetal taurine levels. Taurine-deficiency in the mother leads to growth retardation of the offspring, and to impaired perinatal development of the central nervous system and of the endocrine pancreas. The adult offspring of taurine-deficient mothers display signs of impaired neurological function, impaired glucose tolerance and vascular dysfunction; they may develop gestational diabetes and transmit the effects to the next generation. This transgeneration effect of taurine-deficiency in the perinatal period fits into the concept of fetal origin of adult disease.

Chronic estrogen deficiency leads to molecular aberrations related to neurodegenerative changes in follitropin receptor knockout female mice.

PubMed

Tam, J; Danilovich, N; Nilsson, K; Sairam, M R; Maysinger, D

2002-01-01

The follitropin receptor knockout (FORKO) mouse undergoes ovarian failure, thereby providing an animal model to investigate the consequences of the depletion of circulating estrogen in females. The estrogen deficiency causes marked defects in the female reproductive system, obesity, and skeletal abnormalities. In light of estrogen's known pleiotropic effects in the nervous system, our study examined the effects of genetically induced estrogen-testosterone imbalance on this system in female FORKO mice. Circulating concentrations of 17-beta-estradiol (E2) in FORKO mice are significantly decreased (FORKO -/-: 1.13+/-0.34 pg/ml; wild-type +/+: 17.6+/-3.5 pg/ml, P<0.0001, n=32-41); in contrast, testosterone levels are increased (-/-: 37.7+/-2.3 pg/ml; wild-type +/+: 3.9+/-1.7 pg/ml, P<0.005, n=25-33). The focus was on the activities of key enzymes in the central cholinergic and peripheral nervous systems, on dorsal root ganglia (DRGs) capacity for neurite outgrowth, and on the phosphorylation state of structural neurofilament (NF) proteins. Choline acetyltransferase activity was decreased in several central cholinergic structures (striatum 50+/-3%, hippocampus 24+/-2%, cortex 12+/-3%) and in DRGs (11+/-6%). Moreover, we observed aberrations in the enzymatic activities of mitogen-activated protein kinases (extracellular-regulated kinase and c-Jun N-terminal kinase) in the hippocampus, DRGs, and sciatic nerves. Hippocampal and sensory ganglia samples from FORKO mice contained hyper-phosphorylated NFs. Finally, explanted ganglia of FORKO mice displayed decreased neurite outgrowth (20-50%) under non-treated conditions and when treated with E2 (10 nM). Our results demonstrate that genetic depletion of circulating estrogen leads to biochemical and morphological changes in central and peripheral neurons, and underlie the importance of estrogen in the normal development and functioning of the nervous system. In particular, the findings suggest that an early and persisting

Nutritional management of breastfeeding infants for the prevention of common nutrient deficiencies and excesses

PubMed Central

2011-01-01

Breastfeeding is the best source of nutrition for every infant, and exclusive breastfeeding for 6 months is usually optimal in the common clinical situation. However, inappropriate complementary feeding could lead to a nutrient-deficient status, such as iron deficiency anemia, vitamin D deficiency, and growth faltering. The recent epidemic outbreak of obesity in Korean children emphasizes the need for us to control children's daily sedentary life style and their intakes of high caloric foods in order to prevent obesity. Recent assessment of breastfeeding in Korea has shown that the rate is between 63% and 89%; thus, up-to-dated evidence-based nutritional management of breastfeeding infants to prevent common nutrient deficiencies or excesses should be taught to all clinicians and health care providers. PMID:22025920

The Role of the World Health Organization in Eliminating Iodine Deficiency Worldwide.

PubMed

Karwowska, Paulina; Breda, Joao

2017-01-01

Iodine deficiency has been one of the most prevalent micronutrient deficiencies in the world, causing many health disorders, particularly in pregnant women and children. Despite increased salt iodization in some countries and regions, the process has lacked global coordination and sustainability, two prerequisites for reaching the aim of eliminating iodine deficiency. This goal can be reached only by evidence-based, effectively monitored joint and committed actions of all countries. The aim of the article is to present the role of WHO in leading and coordinating public health actions aiming elimination of iodine deficiency. WHO was given a mandate to coordinate such public health actions, including developing and strengthening relevant public health legislation, issuing technically sound and evidence-based norms and standards, and monitoring the health situation and trends. WHO has coordinated and fostered collaboration between countries, international organizations, scientific associations and non-governmental organization to reach the goal of eliminating iodine deficiency. No recent patents are discussed for this WHO report. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Suppressed translation as a mechanism of initiation of CASP8 (caspase 8)-dependent apoptosis in autophagy-deficient NSCLC cells under nutrient limitation.

PubMed

Allavena, Giulia; Cuomo, Francesca; Baumgartner, Georg; Bele, Tadeja; Sellgren, Alexander Yarar; Oo, Kyaw Soe; Johnson, Kaylee; Gogvadze, Vladimir; Zhivotovsky, Boris; Kaminskyy, Vitaliy O

2018-01-01

Macroautophagy/autophagy inhibition under stress conditions is often associated with increased cell death. We found that under nutrient limitation, activation of CASP8/caspase-8 was significantly increased in autophagy-deficient lung cancer cells, which precedes mitochondria outer membrane permeabilization (MOMP), CYCS/cytochrome c release, and activation of CASP9/caspase-9, indicating that under such conditions the activation of CASP8 is a primary event in the initiation of apoptosis as well as essential to reduce clonogenic survival of autophagy-deficient cells. Starvation leads to suppression of CFLAR proteosynthesis and accumulation of CASP8 in SQSTM1 puncta. Overexpression of CFLARs reduces CASP8 activation and apoptosis during starvation, while its silencing promotes efficient activation of CASP8 and apoptosis in autophagy-deficient U1810 lung cancer cells even under nutrient-rich conditions. Similar to starvation, inhibition of protein translation leads to efficient activation of CASP8 and cell death in autophagy-deficient lung cancer cells. Thus, here for the first time we report that suppressed translation leads to activation of CASP8-dependent apoptosis in autophagy-deficient NSCLC cells under conditions of nutrient limitation. Our data suggest that targeting translational machinery can be beneficial for elimination of autophagy-deficient cells via the CASP8-dependent apoptotic pathway.

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

Heavy Metals Induce Iron Deficiency Responses at Different Hierarchic and Regulatory Levels.

PubMed

Lešková, Alexandra; Giehl, Ricardo F H; Hartmann, Anja; Fargašová, Agáta; von Wirén, Nicolaus

2017-07-01

In plants, the excess of several heavy metals mimics iron (Fe) deficiency-induced chlorosis, indicating a disturbance in Fe homeostasis. To examine the level at which heavy metals interfere with Fe deficiency responses, we carried out an in-depth characterization of Fe-related physiological, regulatory, and morphological responses in Arabidopsis ( Arabidopsis thaliana ) exposed to heavy metals. Enhanced zinc (Zn) uptake closely mimicked Fe deficiency by leading to low chlorophyll but high ferric-chelate reductase activity and coumarin release. These responses were not caused by Zn-inhibited Fe uptake via IRON-REGULATED TRANSPORTER (IRT1). Instead, Zn simulated the transcriptional response of typical Fe-regulated genes, indicating that Zn affects Fe homeostasis at the level of Fe sensing. Excess supplies of cobalt and nickel altered root traits in a different way from Fe deficiency, inducing only transient Fe deficiency responses, which were characterized by a lack of induction of the ethylene pathway. Cadmium showed a rather inconsistent influence on Fe deficiency responses at multiple levels. By contrast, manganese evoked weak Fe deficiency responses in wild-type plants but strongly exacerbated chlorosis in irt1 plants, indicating that manganese antagonized Fe mainly at the level of transport. These results show that the investigated heavy metals modulate Fe deficiency responses at different hierarchic and regulatory levels and that the interaction of metals with physiological and morphological Fe deficiency responses is uncoupled. Thus, this study not only emphasizes the importance of assessing heavy metal toxicities at multiple levels but also provides a new perspective on how Fe deficiency contributes to the toxic action of individual heavy metals. © 2017 American Society of Plant Biologists. All Rights Reserved.

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.

Intestinal alkaline phosphatase deficiency leads to dysbiosis and bacterial translocation in the newborn intestine.

PubMed

Fawley, Jason; Koehler, Shannon; Cabrera, Susan; Lam, Vy; Fredrich, Katherine; Hessner, Martin; Salzman, Nita; Gourlay, David

2017-10-01

Intestinal alkaline phosphatase (IAP) has been shown to help maintain intestinal homeostasis. Decreased expression of IAP has been linked with pediatric intestinal diseases associated with bacterial overgrowth and subsequent inflammation. We hypothesize that the absence of IAP leads to dysbiosis, with increased inflammation and permeability of the newborn intestine. Sprague-Dawley heterozygote IAP cross-matches were bred. Pups were dam fed ad lib and euthanized at weaning. The microbiotas of terminal ileum (TI) and colon was determined by quantitative real-time polymerase chain reaction (qRT-PCR) of subphylum-specific bacterial 16S ribosomal RNA. RT-PCR was performed on TI for inflammatory cytokines. Intestinal permeability was quantified by fluorescein isothiocyanate-dextran permeability and bacterial translocation by qRT-PCR for bacterial 16S ribosomal RNA in mesenteric lymph nodes. Statistical analysis was done by chi-square analysis. All three genotypes had similar concentrations of bacteria in the TI and colon. However, IAP knockout (IAP-KO) had significantly decreased diversity of bacterial species in their colonic stool compared with heterozygous and wild-type (WT). IAP-KO pups had a nonstatistically significant 3.9-fold increased inducible nitric oxide synthase messenger RNA expression compared with WT (IAP-KO, 3.92 ± 1.36; WT, 1.0 ± 0.27; P = 0.03). IAP-KO also had significantly increased bacterial translocation to mesenteric lymph nodes occurred in IAP-KO (IAP-KO, 7625 RFU/g ± 3469; WT, 4957 RFU/g ± 1552; P = 0.04). Furthermore, IAP-KO had increased permeability (IAP-KO, 0.297 mg/mL ± 0.2; WT, 0.189 mg/mL ± 0.15 P = 0.07), but was not statistically significant. Deficiency of IAP in the newborn intestine is associated with dysbiosis and increased inflammation, permeability, and bacterial translocation. Copyright © 2017 Elsevier Inc. All rights reserved.

Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children

PubMed Central

Dufault, Renee; Schnoll, Roseanne; Lukiw, Walter J; LeBlanc, Blaise; Cornett, Charles; Patrick, Lyn; Wallinga, David; Gilbert, Steven G; Crider, Raquel

2009-01-01

Among dietary factors, learning and behavior are influenced not only by nutrients, but also by exposure to toxic food contaminants such as mercury that can disrupt metabolic processes and alter neuronal plasticity. Neurons lacking in plasticity are a factor in neurodevelopmental disorders such as autism and mental retardation. Essential nutrients help maintain normal neuronal plasticity. Nutritional deficiencies, including deficiencies in the long chain polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, the amino acid methionine, and the trace minerals zinc and selenium, have been shown to influence neuronal function and produce defects in neuronal plasticity, as well as impact behavior in children with attention deficit hyperactivity disorder. Nutritional deficiencies and mercury exposure have been shown to alter neuronal function and increase oxidative stress among children with autism. These dietary factors may be directly related to the development of behavior disorders and learning disabilities. Mercury, either individually or in concert with other factors, may be harmful if ingested in above average amounts or by sensitive individuals. High fructose corn syrup has been shown to contain trace amounts of mercury as a result of some manufacturing processes, and its consumption can also lead to zinc loss. Consumption of certain artificial food color additives has also been shown to lead to zinc deficiency. Dietary zinc is essential for maintaining the metabolic processes required for mercury elimination. Since high fructose corn syrup and artificial food color additives are common ingredients in many foodstuffs, their consumption should be considered in those individuals with nutritional deficits such as zinc deficiency or who are allergic or sensitive to the effects of mercury or unable to effectively metabolize and eliminate it from the body. PMID:19860886

Genetic causes and gene–nutrient interactions in mammalian zinc deficiencies: acrodermatitis enteropathica and transient neonatal zinc deficiency as examples.

PubMed

Kasana, Shakhenabat; Din, Jamila; Maret, Wolfgang

2015-01-01

Discovering genetic causes of zinc deficiency has been a remarkable scientific journey. It started with the description of a rare skin disease, its treatment with various agents, the successful therapy with zinc, and the identification of mutations in a zinc transporter causing the disease. The journey continues with defining the molecular and cellular pathways that lead to the symptoms caused by zinc deficiency. Remarkably, at least two zinc transporters from separate protein families are now known to be involved in the genetics of zinc deficiency. One is ZIP4, which is involved in intestinal zinc uptake. Its mutations can cause acrodermatitis enteropathica (AE) with autosomal recessive inheritance. The other one is ZnT2, the transporter responsible for supplying human milk with zinc. Mutations in this transporter cause transient neonatal zinc deficiency (TNZD) with symptoms similar to AE but with autosomal dominant inheritance. The two diseases can be distinguished in affected infants. AE is fatal if zinc is not supplied to the infant after weaning, whereas TNZD is a genetic defect of the mother limiting the supply of zinc in the milk, and therefore the infant usually will obtain enough zinc once weaned. Although these diseases are relatively rare, the full functional consequences of the numerous mutations in ZIP4 and ZnT2 and their interactions with dietary zinc are not known. In particular, it remains unexplored whether some mutations cause milder disease phenotypes or increase the risk for other diseases if dietary zinc requirements are not met or exceeded. Thus, it is not known whether widespread zinc deficiency in human populations is based primarily on a nutritional deficiency or determined by genetic factors as well. This consideration becomes even more significant with regard to mutations in the other 22 human zinc transporters, where associations with a range of diseases, including diabetes, heart disease, and mental illnesses have been observed

Increased anxiety but normal fear and safety learning in orexin-deficient mice.

PubMed

Khalil, Radwa; Fendt, Markus

2017-03-01

The loss of orexin neurons in humans leads to the disease narcolepsy, characterized by daytime sleepiness and cataplexy. Recent data suggest that orexin is also involved in emotional processing. The goal of the present study was to evaluate fear and safety learning as well as unconditioned fear (anxiety) in orexin-deficient animals. Orexin-deficient mice are an established animal model used to investigate the neuropathology and potential treatments for narcolepsy. Here, we present novel data showing that orexin-deficient mice express increased anxiety in the open field, light-dark box test and carnivore odor-induced avoidance, but are normal in fear and safety learning. These findings suggest an important role of orexin in brain areas involved in anxiety. Copyright © 2016 Elsevier B.V. All rights reserved.

Declining blood lead levels and cognitive changes in moderately lead-poisoned children.

PubMed

Ruff, H A; Bijur, P E; Markowitz, M; Ma, Y C; Rosen, J F

1993-04-07

To determine whether chelation therapy or biochemical changes during a lead-lowering intervention was associated with changes in cognitive functioning of moderately lead-poisoned children. It was hypothesized that cognitive performance would improve as blood lead level declined over time. Short-term intervention study with measures obtained before and after intervention. Hospital specialty clinic and university research center. A total of 154 previously untreated children referred to clinic with blood lead levels between 1.21 and 2.66 mumol/L (25 and 55 micrograms/dL) at time of enrollment. Ages ranged from 13 to 87 months. Enrolled children were treated with edetate calcium disodium (EDTA) if eligible and/or with orally administered iron supplement if iron deficient. For all children, housing inspections and abatement procedures were performed as necessary. Score on Bayley Mental Development Scale or Stanford-Binet Intelligence Scale (4th edition). There was no effect of edetate calcium disodium treatment per se. In the short term (7 weeks), changes in blood lead levels were not related to changes in cognitive scores. In the long term (6 months), however, changes in performance were significantly related to changes in blood lead level, even after controlling for confounding variables. The standardized score increased 1 point for every decrease of 0.14 mumol/L (3 micrograms/dL) in blood lead level. The results suggest an association between decreases in blood lead level and cognitive improvements in moderately lead-poisoned children.

Chernobyl and iodine deficiency in the Russian Federation: an environmental disaster leading to a public health opportunity.

PubMed

Jackson, Richard J; DeLozier, David M; Gerasimov, Gregory; Borisova, Olga; Garbe, Paul L; Goultchenko, Lioudmila; Shakarishvili, George; Hollowell, Joseph G; Miller, Dayton T

2002-01-01

The Chernobyl nuclear disaster of April 26, 1986, triggered a chain of devastating events that later included an unexpected increase in childhood thyroid cancer and evidence of iodine deficiency (ID) in Russia. For the Russian people the Chernobyl event had profound psychological impacts, provoking anxiety about nuclear technology and mistrust of governmental control efforts. Frequently in public health a crisis is required to create the political will to manage longstanding problems, and public health officials must rapidly mobilize to take advantage of the opportunity. In this case, ID, previously not seen as a problem in Russia, was recognized to be potentially serious, and the Russian Federation, assisted by the catalytic bi-national effort of the U.S.-Russian Joint Commission on Economic and Technological Cooperation (Gore-Chernomyrdin Commission (GCC)) established a model salt iodization policy, developed a planning process, and implemented a program to prevent ID through a systematic approach that included the people, government, and private groups using open communication, dissemination of the findings, and action plans. By 1999, political will had been mobilized and over 20% of the nation's salt was being iodized, up from about 1% in 1996. Universal iodization of salt was not a specific objective of the GCC; however, the increasing availability of iodized salt is leading to the elimination of ID, which is now a political goal in Russia. The full realization of this goal will require more time for education, marketing, and possibly legislative action.

Leptin deficiency: clinical implications and opportunities for therapeutic interventions.

PubMed

Blüher, Susan; Shah, Sunali; Mantzoros, Christos S

2009-10-01

The discovery of leptin has significantly advanced our understanding of the metabolic importance of adipose tissue and has revealed that both leptin deficiency and leptin excess are associated with severe metabolic, endocrine, and immunological consequences. We and others have shown that a prominent role of leptin in humans is to mediate the neuroendocrine adaptation to energy deprivation. Humans with genetic mutations in the leptin and leptin receptor genes have deregulated food intake and energy expenditure leading to a morbidly obese phenotype and a disrupted regulation in neuroendocrine and immune function and in glucose and fat metabolism. Observational and interventional studies in humans with (complete) congenital leptin deficiency caused by mutations in the leptin gene or with relative leptin deficiency as seen in states of negative energy balance such as lipoatrophy, anorexia nervosa, or exercise-induced hypothalamic and neuroendocrine dysfunction have contributed to the elucidation of the pathophysiological role of leptin in these conditions and of the clinical significance of leptin administration in these subjects. More specifically, interventional studies have demonstrated that several neuroendocrine, metabolic, or immune disturbances in these states could be restored by leptin administration. Leptin replacement therapy is currently available through a compassionate use program for congenital complete leptin deficiency and under an expanded access program to subjects with leptin deficiency associated with congenital or acquired lipoatrophy. In addition, leptin remains a potentially forthcoming treatment for several other states of energy deprivation including anorexia nervosa or milder forms of hypothalamic amenorrhea pending appropriate clinical trials.

Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice

PubMed Central

Ghosh, Shampa; Sinha, Jitendra Kumar; Putcha, Uday Kumar; Raghunath, Manchala

2016-01-01

Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects. PMID:26835453

Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice.

PubMed

Ghosh, Shampa; Sinha, Jitendra Kumar; Putcha, Uday Kumar; Raghunath, Manchala

2016-01-01

Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.

Carnitine Deficiency and Pregnancy

PubMed Central

de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

2015-01-01

We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

PubMed

Kesby, James P; Turner, Karly M; Alexander, Suzanne; Eyles, Darryl W; McGrath, John J; Burne, Thomas H J

2017-11-01

Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat

[EFFICACY OF IVIG TREATMENT IN BRONCHIECTASIS ASSOCIATED WITH IGG SUBCLASS DEFICIENCY].

PubMed

Shostak, Yael; Kramer, Mordechai R

2017-11-01

Bronchiectasis is characterized by an abnormal dilatation of the bronchi leading to a chronic inflammatory process, airway blockage and impaired clearance of secretions. The damage to the airways is usually progressive and is the result of several pathogenic processes. In the past, healing of infections (especially pulmonary tuberculosis) was the main cause of airway dilatation and progression of chronic inflammation. Today, congenital illnesses, anatomical defects and immune deficiency play an important role in the pathogenesis of bronchiectasis formation. The immunoglobulin repertoire is vital for effective host protection against a wide variety of pathogens. Primary antibody deficiency diseases are defects of the humoral arm of the immune system and involve an absence/reduced levels of one or more immunoglobulin classes/subclasses or defects of specific antibody formation. Immunoglobulin G (IGG) subclass deficiency can occur in a healthy person and could be without clinical significance. However, in recent years there is emerging evidence that in patients with recurrent infections, early diagnosis of antibody deficiency affects the prognosis and prevention of ongoing lung damage. The use of IVIG has contributed significantly to the survival rate in primary antibody deficiencies. There is limited literature on the treatment of IVIG for patients with IGG subclass deficiency. However, all studies presented so far demonstrated that immunoglobulin therapy reduced the rate of bacterial infections, days of antibiotic usage, hospital admissions and significantly increased patients' quality of life. Therefore, in the appropriate clinical setting, ie: a patient with bronchiectasis and recurrent infections, it is justified to test whether there are humoral immune defects such as IGG subclass deficiency. In a patient with proven deficiency, we should recommend to start IVIG treatment until clinical benefit is achieved.

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.

SLC20A2 DEFICIENCY IN MICE LEADS TO ELEVATED PHOSPHATE LEVELS IN CEREBROSPINAL FLUID AND GLYMPHATIC PATHWAY-ASSOCIATED ARTERIOLAR CALCIFICATION, AND RECAPITULATES HUMAN IDIOPATHIC BASAL GANGLIA CALCIFICATION

PubMed Central

Wallingford, MC; Chia, J; Leaf, EM; Borgeia, S; Chavkin, NW; Sawangmake, C; Marro, K; Cox, TC; Speer, MY; Giachelli, CM

2016-01-01

Idiopathic basal ganglia calcification is a brain calcification disorder that has been genetically linked to autosomal dominant mutations in the sodium-dependent phosphate co-transporter, SLC20A2. The mechanisms whereby deficiency of Slc20a2 leads to basal ganglion calcification are unknown. In the mouse brain, we found that Slc20a2 was expressed in tissues that produce and/or regulate cerebrospinal fluid, including choroid plexus, ependyma and arteriolar smooth muscle cells. Haploinsufficient Slc20a2 +/− mice developed age-dependent basal ganglia calcification that formed in glymphatic pathway-associated arterioles. Slc20a2 deficiency uncovered phosphate homeostasis dysregulation characterized by abnormally high cerebrospinal fluid phosphate levels and hydrocephalus, in addition to basal ganglia calcification. Slc20a2 siRNA knockdown in smooth muscle cells revealed increased susceptibility to high phosphate-induced calcification. These data suggested that loss of Slc20a2 led to dysregulated phosphate homeostasis and enhanced susceptibility of arteriolar smooth muscle cells to elevated phosphate-induced calcification. Together, dysregulated cerebrospinal fluid phosphate and enhanced smooth muscle cell susceptibility may predispose to glymphatic pathway-associated arteriolar calcification. PMID:26822507

Vitamin K deficiency: a case report and review of current guidelines.

PubMed

Marchili, Maria Rosaria; Santoro, Elisa; Marchesi, Alessandra; Bianchi, Simona; Rotondi Aufiero, Lelia; Villani, Alberto

2018-03-14

Vitamin K, a fat soluble vitamin, is a necessary cofactor for the activation of coagulation factors II, VII, IX, X, and protein C and S. In neonatal period, vitamin K deficiency may lead to Vitamin K Deficiency Bleeding (VKDB). We present the case of a 2 months and 20 days Caucasian male, presented for bleeding from the injections sites of vaccines. At birth oral vitamin K prophylaxis was administered. Neonatal period was normal. He was exclusively breastfed and received a daily oral supplementation with 25 μg of vitamin K. A late onset vitamin K deficiency bleeding was suspected. Intravenous Vitamin K was administered with complete recovery. Nevertheless the oral prophylaxis, our case developed a VKDB: it is necessary to revise the current guidelines in order to standardize timing and dosage in different clinical conditions.

Laryngeal Muscles Are Spared in the Dystrophin Deficient "mdx" Mouse

ERIC Educational Resources Information Center

Thomas, Lisa B.; Joseph, Gayle L.; Adkins, Tracey D.; Andrade, Francisco H.; Stemple, Joseph C.

2008-01-01

Purpose: "Duchenne muscular dystrophy (DMD)" is caused by the loss of the cytoskeletal protein, dystrophin. The disease leads to severe and progressive skeletal muscle wasting. Interestingly, the disease spares some muscles. The purpose of the study was to determine the effects of dystrophin deficiency on 2 intrinsic laryngeal muscles, the…

The effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in hemodialysis patients.

PubMed

Kim, So Mi; Kim, Miyeon; Lee, Eun Kyoung; Kim, Soon Bae; Chang, Jai Won; Kim, Hyun Woo

2016-07-01

Introduction High sodium intake is the main cause of fluid overload in hemodialysis (HD) patients, leading to increased cardiovascular mortality. High sodium intake is known to be associated with low salt taste acuity and/or high preference. As the zinc status could influence taste acuity, we analyzed the effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in HD patients. Methods A total of 77 HD patients was enrolled in this cross-sectional study. Zinc deficiency was defined as serum zinc level with below 70 µg/mL. The patients were divided into two groups based on serum zinc level. Salt taste acuity and preference were determined by a sensory test using varying concentrations of NaCl solution, and dietary sodium intake was estimated using 3-day dietary recall surveys. Findings The mean salt recognition threshold and salt taste preference were significantly higher in the zinc deficient group than in the non-zinc deficient group. And there was significant positive correlation between salt taste preference and dietary sodium intake in zinc deficient group (r = 0.43, P = 0.002). Although, the dietary sodium intake showed a high tendency with no significance (P = 0.052), interdialytic weight gain was significantly higher in the zinc deficient group than in the non-zinc deficient group (2.68 ± 1.02 kg vs. 3.18 ± 1.02 kg; P = 0.047). Discussion Zinc deficiency may be related to low salt taste acuity and high salt preference, leading to high dietary sodium intake in HD patients. © 2016 International Society for Hemodialysis.

Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

PubMed

Lambert, G; Sakai, N; Vaisman, B L; Neufeld, E B; Marteyn, B; Chan, C C; Paigen, B; Lupia, E; Thomas, A; Striker, L J; Blanchette-Mackie, J; Csako, G; Brady, J N; Costello, R; Striker, G E; Remaley, A T; Brewer, H B; Santamarina-Fojo, S

2001-05-04

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

Invertebrate Models for Coenzyme Q10 Deficiency

PubMed Central

Fernández-Ayala, Daniel J.M.; Jiménez-Gancedo, Sandra; Guerra, Ignacio; Navas, Plácido

2014-01-01

The human syndrome of coenzyme Q (CoQ) deficiency is a heterogeneous mitochondrial disease characterized by a diminution of CoQ content in cells and tissues that affects all the electron transport processes CoQ is responsible for, like the electron transference in mitochondria for respiration and ATP production and the antioxidant capacity that it exerts in membranes and lipoproteins. Supplementation with external CoQ is the main attempt to address these pathologies, but quite variable results have been obtained ranging from little response to a dramatic recovery. Here, we present the importance of modeling human CoQ deficiencies in animal models to understand the genetics and the pathology of this disease, although the election of an organism is crucial and can sometimes be controversial. Bacteria and yeast harboring mutations that lead to CoQ deficiency are unable to grow if they have to respire but develop without any problems on media with fermentable carbon sources. The complete lack of CoQ in mammals causes embryonic lethality, whereas other mutations produce tissue-specific diseases as in humans. However, working with transgenic mammals is time and cost intensive, with no assurance of obtaining results. Caenorhabditis elegans and Drosophila melanogaster have been used for years as organisms to study embryonic development, biogenesis, degenerative pathologies, and aging because of the genetic facilities and the speed of working with these animal models. In this review, we summarize several attempts to model reliable human CoQ deficiencies in invertebrates, focusing on mutant phenotypes pretty similar to those observed in human patients. PMID:25126050

The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency.

PubMed

Laron, Zvi

2008-01-01

Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

Acquired color vision deficiency.

PubMed

Simunovic, Matthew P

2016-01-01

Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

Use of Transportable Radiation Detection Instruments to Assess Internal Contamination from Intakes of Radionuclides Part II: Calibration Factors and ICAT Computer Program.

PubMed

Anigstein, Robert; Olsher, Richard H; Loomis, Donald A; Ansari, Armin

2016-12-01

The detonation of a radiological dispersion device or other radiological incidents could result in widespread releases of radioactive materials and intakes of radionuclides by affected individuals. Transportable radiation monitoring instruments could be used to measure radiation from gamma-emitting radionuclides in the body for triaging individuals and assigning priorities to their bioassay samples for in vitro assessments. The present study derived sets of calibration factors for four instruments: the Ludlum Model 44-2 gamma scintillator, a survey meter containing a 2.54 × 2.54-cm NaI(Tl) crystal; the Captus 3000 thyroid uptake probe, which contains a 5.08 × 5.08-cm NaI(Tl) crystal; the Transportable Portal Monitor Model TPM-903B, which contains two 3.81 × 7.62 × 182.9-cm polyvinyltoluene plastic scintillators; and a generic instrument, such as an ionization chamber, that measures exposure rates. The calibration factors enable these instruments to be used for assessing inhaled or ingested intakes of any of four radionuclides: Co, I, Cs, and Ir. The derivations used biokinetic models embodied in the DCAL computer software system developed by the Oak Ridge National Laboratory and Monte Carlo simulations using the MCNPX radiation transport code. The three physical instruments were represented by MCNP models that were developed previously. The affected individuals comprised children of five ages who were represented by the revised Oak Ridge National Laboratory pediatric phantoms, and adult men and adult women represented by the Adult Reference Computational Phantoms described in Publication 110 of the International Commission on Radiological Protection. These calibration factors can be used to calculate intakes; the intakes can be converted to committed doses by the use of tabulated dose coefficients. These calibration factors also constitute input data to the ICAT computer program, an interactive Microsoft Windows-based software package that estimates intakes of

USE OF TRANSPORTABLE RADIATION DETECTION INSTRUMENTS TO ASSESS INTERNAL CONTAMINATION FROM INTAKES OF RADIONUCLIDES PART II: CALIBRATION FACTORS AND ICAT COMPUTER PROGRAM

PubMed Central

Anigstein, Robert; Olsher, Richard H.; Loomis, Donald A.; Ansari, Armin

2017-01-01

The detonation of a radiological dispersion device or other radiological incidents could result in widespread releases of radioactive materials and intakes of radionuclides by affected individuals. Transportable radiation monitoring instruments could be used to measure radiation from gamma-emitting radionuclides in the body for triaging individuals and assigning priorities to their bioassay samples for in vitro assessments. The present study derived sets of calibration factors for four instruments: the Ludlum Model 44-2 gamma scintillator, a survey meter containing a 2.54 × 2.54-cm NaI(Tl) crystal; the Captus 3000 thyroid uptake probe, which contains a 5.08 × 5.08-cm NaI(Tl) crystal; the Transportable Portal Monitor Model TPM-903B, which contains two 3.81 × 7.62 × 182.9-cm polyvinyltoluene plastic scintillators; and a generic instrument, such as an ionization chamber, that measures exposure rates. The calibration factors enable these instruments to be used for assessing inhaled or ingested intakes of any of four radionuclides: 60Co, 131I, 137Cs, and 192Ir. The derivations used biokinetic models embodied in the DCAL computer software system developed by the Oak Ridge National Laboratory and Monte Carlo simulations using the MCNPX radiation transport code. The three physical instruments were represented by MCNP models that were developed previously. The affected individuals comprised children of five ages who were represented by the revised Oak Ridge National Laboratory pediatric phantoms, and adult men and adult women represented by the Adult Reference Computational Phantoms described in Publication 110 of the International Commission on Radiological Protection. These calibration factors can be used to calculate intakes; the intakes can be converted to committed doses by the use of tabulated dose coefficients. These calibration factors also constitute input data to the ICAT computer program, an interactive Microsoft Windows-based software package that estimates

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

Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors.

PubMed

Ortigoza-Escobar, Juan Darío; Alfadhel, Majid; Molero-Luis, Marta; Darin, Niklas; Spiegel, Ronen; de Coo, Irenaeus F; Gerards, Mike; Taylor, Robert W; Artuch, Rafael; Nashabat, Marwan; Rodríguez-Pombo, Pilar; Tabarki, Brahim; Pérez-Dueñas, Belén

2017-09-01

Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330. © 2017 American Neurological Association.

Pyruvate kinase (PK) deficiency in newborns: the pitfalls of diagnosis.

PubMed

Pissard, Serge; de Montalembert, Mariane; Bachir, Dora; Max-Audit, Isabelle; Goossens, Michel; Wajcman, Henri; Bader-Meunier, Brigitte

2007-04-01

Pyruvate kinase (PK) deficiency is asymptomatic in heterozygotes, but it can lead in homozygous neonates to a severe neonatal hemolysis, sometimes life-threatening. We report five cases, with a 1- to 17-month delayed diagnosis, highlighting the need to measure PK activity in neonates and parents in case of an hemolysis at birth.

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…

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.

Betaine deficiency in maize

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

Lerma, C.; Rich, P.J.; Ju, G.C.

1991-04-01

Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency. This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positivemore » and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline {r arrow} betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde.« less

Combinatorial effects of zinc deficiency and arsenic exposure on zebrafish (Danio rerio) development

PubMed Central

Truong, Lisa; Barton, Carrie L.; Chase, Tyler T.; Gonnerman, Greg D.; Wong, Carmen P.; Tanguay, Robert L.; Ho, Emily

2017-01-01

Zinc deficiency and chronic low level exposures to inorganic arsenic in drinking water are both significant public health concerns that affect millions of people including pregnant women. These two conditions can co-exist in the human population but little is known about their interaction, and in particular, whether zinc deficiency sensitizes individuals to arsenic exposure and toxicity, especially during critical windows of development. To address this, we utilized the Danio rerio (zebrafish) model to test the hypothesis that parental zinc deficiency sensitizes the developing embryo to low-concentration arsenic toxicity, leading to altered developmental outcomes. Adult zebrafish were fed defined zinc deficient and zinc adequate diets and were spawned resulting in zinc adequate and zinc deficient embryos. The embryos were treated with environmentally relevant concentrations of 0, 50, and 500 ppb arsenic. Arsenic exposure significantly reduced the amount of zinc in the developing embryo by ~7%. The combination of zinc deficiency and low-level arsenic exposures did not sensitize the developing embryo to increased developmental malformations or mortality. The combination did cause a 40% decline in physical activity of the embryos, and this decline was significantly greater than what was observed with zinc deficiency or arsenic exposure alone. Significant changes in RNA expression of genes that regulate zinc homeostasis, response to oxidative stress and insulin production (including zip1, znt7, nrf2, ogg1, pax4, and insa) were found in zinc deficient, or zinc deficiency and arsenic exposed embryos. Overall, the data suggests that the combination of zinc deficiency and arsenic exposure has harmful effects on the developing embryo and may increase the risk for developing chronic diseases like diabetes. PMID:28837703

Riboflavin transporter deficiency mimicking mitochondrial myopathy caused by complex II deficiency.

PubMed

Nimmo, Graeme A M; Ejaz, Resham; Cordeiro, Dawn; Kannu, Peter; Mercimek-Andrews, Saadet

2018-02-01

Biallelic likely pathogenic variants in SLC52A2 and SLC52A3 cause riboflavin transporter deficiency. It is characterized by muscle weakness, ataxia, progressive ponto-bulbar palsy, amyotrophy, and sensorineural hearing loss. Oral riboflavin halts disease progression and may reverse symptoms. We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8-year-old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss. His muscle biopsy showed complex II deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing revealed a homozygous likely pathogenic variant in SLC52A2 (c.917G>A; p.Gly306Glu). Patient 2 is a 14-month-old boy with global developmental delay, respiratory insufficiency requiring ventilator support within the first year of life. His muscle biopsy revealed combined complex II + III deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing identified a homozygous likely pathogenic variant in SCL52A3 (c.1223G>A; p.Gly408Asp). We report two new patients with riboflavin transporter deficiency, caused by mutations in two different riboflavin transporter genes. Both patients presented with complex II deficiency. This treatable neurometabolic disorder can mimic mitochondrial myopathy. In patients with complex II deficiency, riboflavin transporter deficiency should be included in the differential diagnosis to allow early treatment and improve neurodevelopmental outcome. © 2017 Wiley Periodicals, Inc.

Iron-Deficiency Anemia (For Parents)

MedlinePlus

... Videos for Educators Search English Español Iron-Deficiency Anemia KidsHealth / For Parents / Iron-Deficiency Anemia What's in ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency.

PubMed

Turton, J P; Strom, M; Langham, S; Dattani, M T; Le Tissier, P

2012-03-01

  Mutations in the POU1F1 gene severely affect the development and function of the anterior pituitary gland and lead to combined pituitary hormone deficiency (CPHD).   The clinical and genetic analysis of a patient presenting with CPHD and functional characterization of identified mutations.   We describe a male patient with extreme short stature, learning difficulties, anterior pituitary hypoplasia, secondary hypothyroidism and undetectable prolactin, growth hormone (GH) and insulin-like growth factor 1 (IGF1), with normal random cortisol.   The POU1F1 coding region was amplified by PCR and sequenced; the functional consequence of the mutations was analysed by cell transfection and in vitro assays.   Genetic analysis revealed compound heterozygosity for two novel putative loss of function mutations in POU1F1: a transition at position +3 of intron 1 [IVS1+3nt(A>G)] and a point mutation in exon 6 resulting in a substitution of arginine by tryptophan (R265W). Functional analysis revealed that IVS1+3nt(A>G) results in a reduction in the correctly spliced POU1F1 mRNA, which could be corrected by mutations of the +4, +5 and +6 nucleotides. Analysis of POU1F1(R265W) revealed complete loss of function resulting from severely reduced protein stability.   Combined pituitary hormone deficiency in this patient is caused by loss of POU1F1 function by two novel mechanisms, namely aberrant splicing (IVS1+3nt (A>G) and protein instability (R265W). Identification of the genetic basis of CPHD enabled the cessation of hydrocortisone therapy without the need for further assessment for evolving endocrinopathy. © 2012 Blackwell Publishing Ltd.

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency[S

PubMed Central

Gomaraschi, Monica; Ossoli, Alice; Castelnuovo, Samuela; Simonelli, Sara; Pavanello, Chiara; Balzarotti, Gloria; Arca, Marcello; Di Costanzo, Alessia; Sampietro, Tiziana; Vaudo, Gaetano; Baldassarre, Damiano; Veglia, Fabrizio; Franceschini, Guido; Calabresi, Laura

2017-01-01

The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold, P = 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality. PMID:28351888

Leptin Deficiency: Clinical Implications and Opportunities for Therapeutic Interventions

PubMed Central

Blüher, Susan; Shah, Sunali; Mantzoros, Christos S.

2017-01-01

The discovery of leptin has significantly advanced our understanding of the metabolic importance of adipose tissue and has revealed that both leptin deficiency and leptin excess are associated with severe metabolic, endocrine, and immunological consequences. We and others have shown that a prominent role of leptin in humans is to mediate the neuroendocrine adaptation to energy deprivation. Humans with genetic mutations in the leptin and leptin receptor genes have deregulated food intake and energy expenditure leading to a morbidly obese phenotype and a disrupted regulation in neuroendocrine and immune function and in glucose and fat metabolism. Observational and interventional studies in humans with (complete) congenital leptin deficiency caused by mutations in the leptin gene or with relative leptin deficiency as seen in states of negative energy balance such as lipoatrophy, anorexia nervosa, or exercise-induced hypothalamic and neuroendocrine dysfunction have contributed to the elucidation of the pathophysiological role of leptin in these conditions and of the clinical significance of leptin administration in these subjects. More specifically, interventional studies have demonstrated that several neuroendocrine, metabolic, or immune disturbances in these states could be restored by leptin administration. Leptin replacement therapy is currently available through a compassionate use program for congenital complete leptin deficiency and under an expanded access program to subjects with leptin deficiency associated with congenital or acquired lipoatrophy. In addition, leptin remains a potentially forthcoming treatment for several other states of energy deprivation including anorexia nervosa or milder forms of hypothalamic amenorrhea pending appropriate clinical trials. PMID:19730134

Upregulation of P2RX7 in Cx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration.

PubMed

Hu, Shulong J; Calippe, Bertrand; Lavalette, Sophie; Roubeix, Christophe; Montassar, Fadoua; Housset, Michael; Levy, Olivier; Delarasse, Cecile; Paques, Michel; Sahel, José-Alain; Sennlaub, Florian; Guillonneau, Xavier

2015-05-06

Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists. Copyright © 2015 the authors 0270-6474/15/356987-10$15.00/0.

Boron deficiency inhibits root growth by controlling meristem activity under cytokinin regulation.

PubMed

Poza-Viejo, Laura; Abreu, Isidro; González-García, Mary Paz; Allauca, Paúl; Bonilla, Ildefonso; Bolaños, Luis; Reguera, María

2018-05-01

Significant advances have been made in the last years trying to identify regulatory pathways that control plant responses to boron (B) deficiency. Still, there is a lack of a deep understanding of how they act regulating growth and development under B limiting conditions. Here, we analyzed the impact of B deficit on cell division leading to root apical meristem (RAM) disorganization. Our results reveal that inhibition of cell proliferation under the regulatory control of cytokinins (CKs) is an early event contributing to root growth arrest under B deficiency. An early recovery of QC46:GUS expression after transferring B-deficient seedlings to control conditions revealed a role of B in the maintenance of QC identity whose loss under deficiency occurred at later stages of the stress. Additionally, the D-type cyclin CYCD3 overexpressor and triple mutant cycd3;1-3 were used to evaluate the effect on mitosis inhibition at the G1-S boundary. Overall, this study supports the hypothesis that meristem activity is inhibited by B deficiency at early stages of the stress as it does cell elongation. Likewise, distinct regulatory mechanisms seem to take place depending on the severity of the stress. The results presented here are key to better understand early signaling responses under B deficiency. Copyright © 2018 Elsevier B.V. All rights reserved.

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue.

PubMed

Fiebrich, H-B; Van Den Berg, G; Kema, I P; Links, T P; Kleibeuker, J H; Van Beek, A P; Walenkamp, A M E; Sluiter, W J; De Vries, E G E

2010-12-01

Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels remains unknown. To investigate the prevalence of fat-soluble vitamin deficiencies in long-term somatostatin analogue users. All acromegaly and carcinoid patients using somatostatin analogues for ≥ 18 months visiting the University Medical Center Groningen between December 2008 and April 2009 were eligible. Vitamin levels of fat-soluble vitamins in blood, clinical and vitamin-dependent laboratory parameters were collected. In all, 19 acromegaly and 35 carcinoid patients were included. Twelve patients experienced steatorrhoea; two carcinoid patients experienced night blindness. Forty-two (78%) were deficient for one or more vitamins, and 32% (n = 17) had multiple deficiencies. Deficiencies for vitamin A, D, E, K1 and E in erythrocytes occurred in 6%, 28%, 15%, 63% and 58% of the patients. Prevalence of vitamin D, E and K1 deficiencies was similar in both patient groups. Treatment duration did not influence vitamin levels. The length of intestinal resection and age correlated negatively with vitamin A levels. Fat-soluble vitamin deficiencies are frequent during long-term somatostatin analogue treatment. Therefore, fat-soluble vitamins should be monitored in these patients. © 2010 Blackwell Publishing Ltd.

CNGA3 deficiency affects cone synaptic terminal structure and function and leads to secondary rod dysfunction and degeneration.

PubMed

Xu, Jianhua; Morris, Lynsie M; Michalakis, Stylianos; Biel, Martin; Fliesler, Steven J; Sherry, David M; Ding, Xi-Qin

2012-03-01

To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency. Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3-/- mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy. The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3-/- mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3-/- retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%-40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin α-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3-/- retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months. These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised.

SLAP deficiency decreases dsDNA autoantibody production

PubMed Central

Peterson, Lisa K.; Pennington, Luke F.; Shaw, Laura A.; Brown, Meredith; Treacy, Eric C.; Friend, Samantha F.; Hatlevik, Øyvind; Rubtsova, Kira; Rubtsov, Anatoly V.; Dragone, Leonard L.

2014-01-01

Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP−/− mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP−/− 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection. PMID:24440645

SLAP deficiency decreases dsDNA autoantibody production.

PubMed

Peterson, Lisa K; Pennington, Luke F; Shaw, Laura A; Brown, Meredith; Treacy, Eric C; Friend, Samantha F; Hatlevik, Øyvind; Rubtsova, Kira; Rubtsov, Anatoly V; Dragone, Leonard L

2014-02-01

Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP(-/-) mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP(-/-) 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection. Copyright © 2013 Elsevier Inc. All rights reserved.

Presentation, diagnosis and management of limbal stem cell deficiency.

PubMed

Sejpal, Kunjal; Bakhtiari, Pejman; Deng, Sophie X

2013-01-01

The human corneal surface epithelium is continuously repopulated by the limbal stem cells (LSCs). Limbal Stem Cell Deficiency (LSCD) can lead to corneal opacity and vascularization, with consequent visual impairment or blindness. Many acquired and congenital diseases can lead to LCSD by direct injury to the LSCs, destruction of LSC niche, or both. Based on the severity of the disease, LSCD can present with various symptoms and signs. Although LSCD can be detected clinically, laboratory tests are necessary to confirm the diagnosis and monitor the disease progression. This article concisely reviews the clinical presentation, techniques for diagnosis and management of LSCD.

In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency.

PubMed

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography-tandem mass spectrometry. Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. Our findings provide strong

Deficiency of the Chemotactic Factor Inactivator in Human Sera with α1-Antitrypsin Deficiency

PubMed Central

Ward, Peter A.; Talamo, Richard C.

1973-01-01

As revealed by appropriate fractionation procedures, human serum deficient in α1-antitrypsin (α1-AT) is also deficient in the naturally occurring chemotactic factor inactivator. These serum donors had severe pulmonary emphysema. Serum from patients with clinically similar pulmonary disease, but with presence of α1-AT in the serum, showed no such deficiency of the chemotactic factor inactivator. When normal human serum and α1-AT-deficient human sera are chemotactically activated by incubation with immune precipitates, substantially more chemotactic activity is generated in α1-AT-deficient serum. These data indicate that in α1-AT-deficient serum there is an imbalance in the generation and control of chemotactic factors. It is suggested that the theory regarding development of pulmonary emphysema in patients lacking the α1-antitrypsin in their serum should be modified to take into account a deficiency of the chemotactic factor inactivator. PMID:4683887

Porin Deficiency in Carbapenem-Resistant Enterobacter aerogenes Strains.

PubMed

Hao, Min; Ye, Meiping; Shen, Zhen; Hu, Fupin; Yang, Yang; Wu, Shi; Xu, Xiaogang; Zhu, Sihui; Qin, Xiaohua; Wang, Minggui

2018-03-13

The more frequent reports of carbapenem-resistant Enterobacteriaceae have raised the alarm for public health. Apart from the production of carbapenemases, deficiency (decreased or loss of expression) of outer membrane proteins (OMPs) has been proposed as a potentially important mechanism of carbapenem resistance. The aim of the present study was to evaluate the contribution of the major OMPs to carbapenem resistance in Enterobacter aerogenes (CREA) isolates and also investigate the role of small RNAs (sRNAs) in inducing porin-associated permeability defects. The differential expression of OMPs was analyzed in four clinical CREA isolates. omp35 and omp36 genes were further investigated by whole-genome sequencing, induction of meropenem resistance, sRNA overexpression, OMP complementation assays, and reverse transcription-quantitative PCR. All four isolates examined were deficient in omp35 and omp36. Functional restoration of these two genes confirmed their contribution to carbapenem resistance. The meropenem induction assay further revealed that porin deficiency plays a role in carbapenem resistance under antibiotic selection pressure. Single-point mutations in omp36 leading to premature stop codons were detected in two of the isolates. Elevated expression levels of the sRNAs micF and micC were detected in the other two porin-deficient isolates, which were predicted to be potential porin regulators from whole-genome sequencing. Overexpression of micF and micC downregulated the expression of Omp35 and Omp36, respectively. Porin deficiency plays an important role in carbapenem resistance among clinical E. aerogenes isolates under regulation of the sRNAs micC and micF. Furthermore, overexpression of micC and micF had a minor to no impact on carbapenem minimum inhibitory concentrations, and thus, the regulatory mechanism is likely to be complex.

Hyperphagia and Obesity in Prader⁻Willi Syndrome: PCSK1 Deficiency and Beyond?

PubMed

Ramos-Molina, Bruno; Molina-Vega, María; Fernández-García, José C; Creemers, John W

2018-06-07

Prader⁻Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment. Proprotein convertase subtilisin/kexin type 1 ( PCSK1 ) deficiency, a rare recessive congenital disorder, partially overlaps phenotypically with PWS, but both genetic disorders show clear dissimilarities as well. The recent observation that PCSK1 is downregulated in a model of human PWS suggests that overlapping pathways are affected. In this review we will not only discuss the mechanisms by which PWS and PCSK1 deficiency could lead to hyperphagia but also the therapeutic interventions to treat obesity in both genetic disorders.

Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants.

PubMed

Sirohi, Gunjan; Pandey, Bipin K; Deveshwar, Priyanka; Giri, Jitender

2016-03-01

Diverse environmental stimuli largely affect the ionic balance of soil, which have a direct effect on growth and crop yield. Details are fast emerging on the genetic/molecular regulators, at whole-genome levels, of plant responses to mineral deficiencies in model and crop plants. These genetic regulators determine the root architecture and physiological adaptations for better uptake and utilization of minerals from soil. Recent evidence also shows the potential roles of epigenetic mechanisms in gene regulation, driven by minerals imbalance. Mineral deficiency or sufficiency leads to developmental plasticity in plants for adaptation, which is preceded by a change in the pattern of gene expression. Notably, such changes at molecular levels are also influenced by altered chromatin structure and methylation patterns, or involvement of other epigenetic components. Interestingly, many of the changes induced by mineral deficiency are also inheritable in the form of epigenetic memory. Unravelling these mechanisms in response to mineral deficiency would further advance our understanding of this complex plant response. Further studies on such approaches may serve as an exciting interaction model of epigenetic and genetic regulations of mineral homeostasis in plants and designing strategies for crop improvement.

1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency.

PubMed

Sijens, Paul E; Rödiger, Lars A; Meiners, Linda C; Lunsing, Roelineke J

2008-05-01

In monocarboxylate transporter 8 (MCT8) gene deficiency, a syndrome combining thyroid and neurological abnormalities, the central nervous system has not yet been characterized by magnetic resonance (MR) spectroscopy. We studied whether the degree of dysmyelinization in MCT8 gene deficiency according to MR imaging (MRI) is coupled with abnormalities in brain metabolism. MRI and MR spectroscopy of the brain were performed twice in two MCT8 gene deficiency patients, for the first time at age 8-10 months and for the second time at age 17-28 months. The results were compared with those obtained in controls of a similar age. Compared with controls, young children with MCT8 show choline and myoinositol level increases and N-acetyl aspartate decreases in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization according to MRI. MCT8 gene deficiency results in deviant myelinization and general atrophy, which is substantiated by the MR spectroscopy findings of increased choline and myoinositol levels and decreased N-acetyl aspartate. The observations suggest that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism.

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.

BLM helicase facilitates telomere replication during leading strand synthesis of telomeres

PubMed Central

Kosiyatrakul, Settapong T.

2015-01-01

Based on its in vitro unwinding activity on G-quadruplex (G4) DNA, the Bloom syndrome–associated helicase BLM is proposed to participate in telomere replication by aiding fork progression through G-rich telomeric DNA. Single molecule analysis of replicated DNA (SMARD) was used to determine the contribution of BLM helicase to telomere replication. In BLM-deficient cells, replication forks initiating from origins within the telomere, which copy the G-rich strand by leading strand synthesis, moved slower through the telomere compared with the adjacent subtelomere. Fork progression through the telomere was further slowed in the presence of a G4 stabilizer. Using a G4-specific antibody, we found that deficiency of BLM, or another G4-unwinding helicase, the Werner syndrome-associated helicase WRN, resulted in increased G4 structures in cells. Importantly, deficiency of either helicase led to greater increases in G4 DNA detected in the telomere compared with G4 seen genome-wide. Collectively, our findings are consistent with BLM helicase facilitating telomere replication by resolving G4 structures formed during copying of the G-rich strand by leading strand synthesis. PMID:26195664

CNGA3 Deficiency Affects Cone Synaptic Terminal Structure and Function and Leads to Secondary Rod Dysfunction and Degeneration

PubMed Central

Xu, Jianhua; Morris, Lynsie M.; Michalakis, Stylianos; Biel, Martin; Fliesler, Steven J.; Sherry, David M.

2012-01-01

Purpose. To investigate rod function and survival after cone dysfunction and degeneration in a mouse model of cone cyclic nucleotide-gated (CNG) channel deficiency. Methods. Rod function and survival in mice with cone CNG channel subunit CNGA3 deficiency (CNGA3−/− mice) were evaluated by electroretinographic (ERG), morphometric, and Western blot analyses. The arrangement, integrity, and ultrastructure of photoreceptor terminals were investigated by immunohistochemistry and electron microscopy. Results. The authors found loss of cone function and cone death accompanied by impairment of rods and rod-driven signaling in CNGA3−/− mice. Scotopic ERG b-wave amplitudes were reduced by 15% at 1 month, 30% at 6 months, and 40% at 9 months and older, while scotopic a-wave amplitudes were decreased by 20% at 9 months, compared with ERGs of age-matched wild-type mice. Outer nuclear layer thickness in CNGA3−/− retina was reduced by 15% at 12 months compared with age-matched wild-type controls. This was accompanied by a 30%–40% reduction in expression of rod-specific proteins, including rhodopsin, rod transducin α-subunit, and glutamic acid-rich protein (GARP). Cone terminals in the CNGA3−/− retina showed a progressive loss of neurochemical and ultrastructural integrity. Abnormalities were observed as early as 1 month. Disorganized rod terminal ultrastructure was noted by 12 months. Conclusions. These findings demonstrate secondary rod impairment and degeneration after cone degeneration in mice with cone CNG channel deficiency. Loss of cone phototransduction accompanies the compromised integrity of cone terminals. With time, rod synaptic structure, function, and viability also become compromised. PMID:22247469

AAV-mediated gene therapy in Dystrophin-Dp71 deficient mouse leads to blood-retinal barrier restoration and oedema reabsorption.

PubMed

Vacca, Ophélie; Charles-Messance, Hugo; El Mathari, Brahim; Sene, Abdoulaye; Barbe, Peggy; Fouquet, Stéphane; Aragón, Jorge; Darche, Marie; Giocanti-Aurégan, Audrey; Paques, Michel; Sahel, José-Alain; Tadayoni, Ramin; Montañez, Cecilia; Dalkara, Deniz; Rendon, Alvaro

2016-07-15

Dystrophin-Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller cells that provide a mechanical link at the Müller cell membrane by direct binding to actin and a transmembrane protein complex. Its absence has been related to blood-retinal barrier (BRB) permeability through delocalization and down-regulation of the AQP4 and Kir4.1 channels (1). We have previously shown that the adeno-associated virus (AAV) variant, ShH10, transduces Müller cells in the Dp71-null mouse retina efficiently and specifically (2,3). Here, we use ShH10 to restore Dp71 expression in Müller cells of Dp71 deficient mouse to study molecular and functional effects of this restoration in an adult mouse displaying retinal permeability. We show that strong and specific expression of exogenous Dp71 in Müller cells leads to correct localization of Dp71 protein restoring all protein interactions in order to re-establish a proper functional BRB and retina homeostasis thus preventing retina from oedema. This study is the basis for the development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular oedema such as diabetic retinopathy (DR). © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Heavy Metals Induce Iron Deficiency Responses at Different Hierarchic and Regulatory Levels1[OPEN

PubMed Central

2017-01-01

In plants, the excess of several heavy metals mimics iron (Fe) deficiency-induced chlorosis, indicating a disturbance in Fe homeostasis. To examine the level at which heavy metals interfere with Fe deficiency responses, we carried out an in-depth characterization of Fe-related physiological, regulatory, and morphological responses in Arabidopsis (Arabidopsis thaliana) exposed to heavy metals. Enhanced zinc (Zn) uptake closely mimicked Fe deficiency by leading to low chlorophyll but high ferric-chelate reductase activity and coumarin release. These responses were not caused by Zn-inhibited Fe uptake via IRON-REGULATED TRANSPORTER (IRT1). Instead, Zn simulated the transcriptional response of typical Fe-regulated genes, indicating that Zn affects Fe homeostasis at the level of Fe sensing. Excess supplies of cobalt and nickel altered root traits in a different way from Fe deficiency, inducing only transient Fe deficiency responses, which were characterized by a lack of induction of the ethylene pathway. Cadmium showed a rather inconsistent influence on Fe deficiency responses at multiple levels. By contrast, manganese evoked weak Fe deficiency responses in wild-type plants but strongly exacerbated chlorosis in irt1 plants, indicating that manganese antagonized Fe mainly at the level of transport. These results show that the investigated heavy metals modulate Fe deficiency responses at different hierarchic and regulatory levels and that the interaction of metals with physiological and morphological Fe deficiency responses is uncoupled. Thus, this study not only emphasizes the importance of assessing heavy metal toxicities at multiple levels but also provides a new perspective on how Fe deficiency contributes to the toxic action of individual heavy metals. PMID:28500270

Intelligent computer-aided training authoring environment

NASA Technical Reports Server (NTRS)

Way, Robert D.

1994-01-01

Although there has been much research into intelligent tutoring systems (ITS), there are few authoring systems available that support ITS metaphors. Instructional developers are generally obliged to use tools designed for creating on-line books. We are currently developing an authoring environment derived from NASA's research on intelligent computer-aided training (ICAT). The ICAT metaphor, currently in use at NASA has proven effective in disciplines from satellite deployment to high school physics. This technique provides a personal trainer (PT) who instructs the student using a simulated work environment (SWE). The PT acts as a tutor, providing individualized instruction and assistance to each student. Teaching in an SWE allows the student to learn tasks by doing them, rather than by reading about them. This authoring environment will expedite ICAT development by providing a tool set that guides the trainer modeling process. Additionally, this environment provides a vehicle for distributing NASA's ICAT technology to the private sector.

Induction of SHP2 deficiency in chondrocytes causes severe scoliosis and kyphosis in mice.

PubMed

Kim, Harry K W; Aruwajoye, Olumide; Sucato, Daniel; Richards, B Stephens; Feng, Gen-Sheng; Chen, Di; King, Philip D; Kamiya, Nobuhiro

2013-10-01

Genetic engineering techniques were used to develop an animal model of juvenile scoliosis during a postnatal skeletal-growth stage. To investigate the effect of targeted SHP2 (Src homology-2) deficiency in chondrocytes on the development of scoliosis during a juvenile growth stage in mice. Juvenile idiopathic scoliosis can lead to progressive severe spinal deformity. The pathophysiology and molecular mechanisms responsible for the deformity are unknown. Here, we investigated the role of SHP2 deficiency in chondrocytes as a potential cause of juvenile scoliosis. Genetically engineered mice with inducible deletion of SHP2 in chondrocytes were generated. The SHP2 function in chondrocytes was inactivated during a juvenile growth stage from the mouse age of 4 weeks. Radiographical, micro-computed tomographic, and histological assessments were used to analyze spinal changes. When SHP2 deficiency was induced during the juvenile stage, a progressive kyphoscoliotic deformity (thoracic lordosis and thoracolumbar kyphoscoliosis) developed within 2 weeks of the initiation of SHP2 deficiency. The 3-dimensional micro-computed tomography analysis confirmed the kyphoscoliotic deformity with a rotational deformity of the spine and osteophyte formation. The histological analysis revealed disorganization of the vertebral growth plate cartilage. Interestingly, when SHP2 was disrupted during the adolescent to adult stages, no spinal deformity developed. SHP2 plays an important role in normal spine development during skeletal maturation. Chondrocyte-specific deletion of SHP2 at a juvenile stage produced a kyphoscoliotic deformity. This new mouse model will be useful for future investigations of the role of SHP2 deficiency in chondrocytes as a mechanism leading to the development of juvenile scoliosis. N/A.

An Elevation in Physical Coupling of Type 1 IP3 Receptors to TRPC3 Channels Constricts Mesenteric Arteries in Genetic Hypertension

PubMed Central

Adebiyi, Adebowale; Thomas-Gatewood, Candice M.; Leo, M. Dennis; Kidd, Michael W.; Neeb, Zachary P.; Jaggar, Jonathan H.

2013-01-01

Hypertension is associated with an elevation in agonist-induced vasoconstriction, but mechanisms involved require further investigation. Many vasoconstrictors bind to phospholipase C-coupled receptors, leading to an elevation in inositol 1,4,5-trisphosphate (IP3) that activates sarcoplasmic reticulum (SR) IP3 receptors (IP3Rs). In cerebral artery myocytes, IP3Rs release SR Ca2+ and can physically couple to canonical transient receptor potential 3 (TRPC3) channels in a caveolin-1-containing macromolecular complex, leading to cation current (ICat) activation that stimulates vasoconstriction. Here, we investigated mechanisms by which IP3Rs control vascular contractility in systemic arteries and IP3R involvement in elevated agonist-induced vasoconstriction during hypertension. Total and plasma membrane-localized TRPC3 protein was ~2.7- and 2-fold higher in mesenteric arteries of hypertensive spontaneously hypertensive rats (SHR) than in Wistar-Kyoto (WKY) rat controls, respectively. In contrast, IP3R1, TRPC1, TRPC6, and caveolin-1 expression was similar. TRPC3 expression was also similar in arteries of pre-hypertensive SHR and WKY rats. Control, IP3- and endothelin-1 (ET-1)-induced FRET between IP3R1 and TRPC3 was higher in hypertensive SHR than WKY myocytes. IP3-induced ICat was ~3-fold larger in SHR myocytes. Pyr3, a selective TRPC3 channel blocker, and CIRBP-TAT, an IP3R-TRP physical coupling inhibitor, reduced IP3-induced ICat and ET-1-induced vasoconstriction more in SHR than WKY myocytes and arteries. Thapsigargin, a SR Ca2+-ATPase blocker, did not alter ET-1-stimulated vasoconstriction in SHR or WKY arteries. These data indicate that ET-1 stimulates physical coupling of IP3R1 to TRPC3 channels in mesenteric artery myocytes, leading to vasoconstriction. Furthermore, an elevation in IP3R1 to TRPC3 channel molecular coupling augments ET-1-induced vasoconstriction during hypertension. PMID:23045459

Experimental Copper Deficiency, Chromium Deficiency and Additional Molybdenum Supplementation in Goats – Pathological Findings

PubMed Central

Aupperle, H; Schoon, HA; Frank, A

2001-01-01

Secondary copper (Cu) deficiency, chromium (Cr) deficiency and molybdenosis (Mo) has been suggested to cause the "mysterious" moose disease in the southwest of Sweden. The present experiment was performed on goats to investigate the clinical, chemical, and pathological alterations after 20 months feeding of a semi-synthetic diet deficient in Cu and Cr. Four groups were included in the study: control group (n = 4), Cu-deficient group (group 1, n = 4), Cr-deficient group (group 2, n = 2) and Cu+Cr-deficient group (group 3, n = 3). Group 3 was additionally supplemented with tetrathiomolybdate during the last 2 months of the experiment. Main histopathological findings in groups 1 and 3 were the lesions in the liver, characterised by a severe active fibrosis, bile duct proliferation, haemosiderosis and mild necroses. Additionally, degenerative alterations of the exocrine pancreas were prominent in groups 1 and 3. Lesions in group 3 were more pronounced than in group 1. In group 3, the skin showed an atrophic dermatosis, while in group 2 a crusty dermatitis caused by Candida spp. was observed. This study shows that liver, pancreas and skin are mainly affected by a long term deficiency of copper and the findings are complicated by molybdenum application while chromium deficiency produced no histomorphological effects in our study. PMID:11887391

The Role of Magnesium Deficiency in Cardiovascular and Intestinal Inflammation

PubMed Central

Weglicki, William B.; Mak, Iu Tong; Chmielinska, Joanna J.; Tejero-Taldo, Maria Isabel; Komarov, Andrei; Kramer, Jay H.

2013-01-01

Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation. We have investigated dietary-induced magnesium deficiency in rodent models to assess the pathobiology associated with prolonged hypomagnesemia. We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure. We have used drugs that block the release of SP from neurons and SP-receptor blockers to prevent some of these pathobiological changes; whereas, blocking SP catabolism enhances inflammation. Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy. PMID:20971697

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.

Progression from isolated growth hormone deficiency to combined pituitary hormone deficiency.

PubMed

Cerbone, Manuela; Dattani, Mehul T

2017-12-01

Growth hormone deficiency (GHD) can present at any time of life from the neonatal period to adulthood, as a result of congenital or acquired insults. It can present as an isolated problem (IGHD) or in combination with other pituitary hormone deficiencies (CPHD). Pituitary deficits can evolve at any time from GHD diagnosis. The number, severity and timing of occurrence of additional endocrinopathies are highly variable. The risk of progression from IGHD to CPHD in children varies depending on the etiology (idiopathic vs organic). The highest risk is displayed by children with abnormalities in the Hypothalamo-Pituitary (H-P) region. Heterogeneous data have been reported on the type and timing of onset of additional pituitary hormone deficits, with TSH deficiency being most frequent and Diabetes Insipidus the least frequent additional deficit in the majority, but not all, of the studies. ACTH deficiency may gradually evolve at any time during follow-up in children or adults with childhood onset IGHD, particularly (but not only) in presence of H-P abnormalities and/or TSH deficiency. Hence there is a need in these patients for lifelong monitoring for ACTH deficiency. GH treatment unmasks central hypothyroidism mainly in patients with organic GHD, but all patients starting GH should have their thyroid function monitored closely. Main risk factors for development of CPHD include organic etiology, H-P abnormalities (in particular pituitary stalk abnormalities, empty sella and ectopic posterior pituitary), midline brain (corpus callosum) and optic nerves abnormalities, genetic defects and longer duration of follow-up. The current available evidence supports longstanding recommendations for the need, in all patients diagnosed with IGHD, of a careful and indefinite follow-up for additional pituitary hormone deficiencies. Copyright © 2017 Elsevier Ltd. All rights reserved.

In HepG2 Cells, Coexisting Carnitine Deficiency Masks Important Indicators of Marginal Biotin Deficiency123

PubMed Central

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

Background: A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. Objective: In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. Methods: We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography–tandem mass spectrometry. Results: Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased

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 and malaria: cytochemical detection of heterozygous G6PD deficiency in women.

PubMed

Peters, Anna L; Van Noorden, Cornelis J F

2009-11-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a X-chromosomally transmitted disorder of the erythrocyte that affects 400 million people worldwide. Diagnosis of heterozygously-deficient women is complicated: as a result of lyonization, these women have a normal and a G6PD-deficient population of erythrocytes. The cytochemical assay is the only reliable assay to discriminate between heterozygously-deficient women and non-deficient women or homozygously-deficient women. G6PD deficiency is mainly found in areas where malaria is or has been endemic. In these areas, malaria is treated with drugs that can cause (severe) hemolysis in G6PD-deficient individuals. A cheap and reliable test is necessary for diagnosing the deficiency to prevent hemolytic disorders when treating malaria. In this review, it is concluded that the use of two different tests for diagnosing men and women is the ideal approach to detect G6PD deficiency. The fluorescent spot test is inexpensive and easy to perform but only reliable for discriminating hemizygous G6PD-deficient men from non-deficient men. For women, the cytochemical assay is recommended. However, this assay is more expensive and difficult to perform and should be simplified into a kit for use in developing countries.

Aromatase Deficient Female Mice Demonstrate Altered Expression of Molecules Critical for Renal Calcium Reabsorption

NASA Astrophysics Data System (ADS)

Öz, Orhan K.; Hajibeigi, Asghar; Cummins, Carolyn; van Abel, Monique; Bindels, René J.; Kuro-o, Makoto; Pak, Charles Y. C.; Zerwekh, Joseph E.

2007-04-01

The incidence of kidney stones increases in women after the menopause, suggesting a role for estrogen deficiency. In order to determine if estrogen may be exerting an effect on renal calcium reabsorption, we measured urinary calcium excretion in the aromatase-deficient female mouse (ArKO) before and following estrogen therapy. ArKO mice had hypercalciuria that corrected during estrogen administration. To evaluate the mechanism by which estrogen deficiency leads to hypercalciuria, we examined the expression of several proteins involved in distal tubule renal calcium reabsorption, both at the message and protein levels. Messenger RNA levels of TRPV5, TRPV6, calbindin-D28K, the Na+/Ca++ exchanger (NCX1), and the plasma membrane calcium ATPase (PMCA1b) were significantly decreased in kidneys of ArKO mice. On the other hand, klotho mRNA levels were elevated in kidneys of ArKO mice. ArKO renal protein extracts had lower levels of calbindin-D28K but higher levels of the klotho protein. Immunochemistry demonstrated increased klotho expression in ArKO kidneys. Estradiol therapy normalized the expression of TRPV5, calbindin-D28K, PMCA1b and klotho. Taken together, these results demonstrate that estrogen deficiency produced by aromatase inactivation is sufficient to produce a renal leak of calcium and consequent hypercalciuria. This may represent one mechanism leading to the increased incidence of kidney stones following the menopause in women.

Iron deficiency anemia

MedlinePlus

Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis.

PubMed

Parkman, Henry P; Yates, Katherine P; Hasler, William L; Nguyan, Linda; Pasricha, Pankaj J; Snape, William J; Farrugia, Gianrico; Calles, Jorge; Koch, Kenneth L; Abell, Thomas L; McCallum, Richard W; Petito, Dorothy; Parrish, Carol Rees; Duffy, Frank; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James; Hamilton, Frank

2011-08-01

Gastroparesis can lead to food aversion, poor oral intake, and subsequent malnutrition. We characterized dietary intake and nutritional deficiencies in patients with diabetic and idiopathic gastroparesis. Patients with gastroparesis on oral intake (N = 305) were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry and completed diet questionnaires at 7 centers. Medical history, gastroparesis symptoms, answers to the Block Food Frequency Questionnaire, and gastric emptying scintigraphy results were analyzed. Caloric intake averaged 1168 ± 801 kcal/day, amounting to 58% ± 39% of daily total energy requirements (TER). A total of 194 patients (64%) reported caloric-deficient diets, defined as <60% of estimated TER. Only 5 patients (2%) followed a diet suggested for patients with gastroparesis. Deficiencies were present in several vitamins and minerals; patients with idiopathic disorders were more likely to have diets with estimated deficiencies in vitamins A, B(6), C, K, iron, potassium, and zinc than diabetic patients. Only one-third of patients were taking multivitamin supplements. More severe symptoms (bloating and constipation) were characteristic of patients who reported an energy-deficient diet. Overall, 32% of patients had nutritional consultation after the onset of gastroparesis; consultation was more likely among patients with longer duration of symptoms and more hospitalizations and patients with diabetes. Multivariable logistic regression analysis indicated that nutritional consultation increased the chances that daily TER were met (odds ratio, 1.51; P = .08). Many patients with gastroparesis have diets deficient in calories, vitamins, and minerals. Nutritional consultation is obtained infrequently but is suggested for dietary therapy and to address nutritional deficiencies. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD).

PubMed

Prasad, Rathi; Chan, Li F; Hughes, Claire R; Kaski, Juan P; Kowalczyk, Julia C; Savage, Martin O; Peters, Catherine J; Nathwani, Nisha; Clark, Adrian J L; Storr, Helen L; Metherell, Louise A

2014-08-01

Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis. We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD. Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis. The study was conducted on patients from three pediatric centers in the United Kingdom. Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study. There were no interventions. Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured. A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line. In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

NADPH Oxidase Deficiency: A Multisystem Approach

PubMed Central

Cicalese, Maria Pia; Delmonte, Ottavia; Migliavacca, Maddalena; Cirillo, Emilia; Violi, Francesco

2017-01-01

The immune system is a complex system able to recognize a wide variety of host agents, through different biological processes. For example, controlled changes in the redox state are able to start different pathways in immune cells and are involved in the killing of microbes. The generation and release of ROS in the form of an “oxidative burst” represent the pivotal mechanism by which phagocytic cells are able to destroy pathogens. On the other hand, impaired oxidative balance is also implicated in the pathogenesis of inflammatory complications, which may affect the function of many body systems. NADPH oxidase (NOX) plays a pivotal role in the production of ROS, and the defect of its different subunits leads to the development of chronic granulomatous disease (CGD). The defect of the different NOX subunits in CGD affects different organs. In this context, this review will be focused on the description of the effect of NOX2 deficiency in different body systems. Moreover, we will also focus our attention on the novel insight in the pathogenesis of immunodeficiency and inflammation-related manifestations and on the protective role of NOX2 deficiency against the development of atherosclerosis. PMID:29430280

Subacute copper-deficiency myelopathy in a patient with occult celiac disease.

PubMed

Cavallieri, Francesco; Fini, Nicola; Contardi, Sara; Fiorini, Massimo; Corradini, Elena; Valzania, Franco

2017-07-01

Acquired copper deficiency represents a rare cause of progressive myelopathy presenting with sensory ataxia and spastic gait. The time interval from neurological symptoms onset to diagnosis of myelopathy ranges from 2 months to several years in almost all cases, mimicking the clinical course of subacute combined degeneration due to vitamin B12 deficiency. A 60-year-old man, without any gastrointestinal symptoms, developed over the course of one week rapidly progressive gait imbalance, tingling and numbness in his feet and ascending lower limb weakness. Spine magnetic resonance imaging revealed hyperintensity involving cervical and dorsal posterior columns of spinal cord. Blood analysis revealed undetectable serum copper levels, low serum ceruloplasmin and positive serum Immunoglobulin A anti-tissue transglutaminase. Upper gastrointestinal endoscopy was performed revealing duodenal villous atrophy consistent with a malabsorption pattern. A gluten-free diet in association with intravenous then oral copper supplementation prompted sustained normalization of serum copper levels and progressive clinical improvement. We report a rare case of myelopathy induced by copper deficiency secondary to undiagnosed celiac disease, peculiarly presenting with a subacute onset. This case expands the neurological presentation and clinical course of myelopathy due to acquired copper deficiency. We suggest investigation of copper deficiency in patients presenting with subacute or even acute sensory ataxia and spastic gait. Detection of hypocupremia in patients without a previous history of gastric surgery should lead to diagnostic testing for celiac disease even in the absence of any obvious gastrointestinal symptoms.

PLAG1 deficiency impairs spermatogenesis and sperm motility in mice.

PubMed

Juma, Almas R; Grommen, Sylvia V H; O'Bryan, Moira K; O'Connor, Anne E; Merriner, D Jo; Hall, Nathan E; Doyle, Stephen R; Damdimopoulou, Pauliina E; Barriga, Daniel; Hart, Adam H; Van de Ven, Wim J M; De Groef, Bert

2017-07-13

Deficiency in pleomorphic adenoma gene 1 (PLAG1) leads to reduced fertility in male mice, but the mechanism by which PLAG1 contributes to reproduction is unknown. To investigate the involvement of PLAG1 in testicular function, we determined (i) the spatial distribution of PLAG1 in the testis using X-gal staining; (ii) transcriptomic consequences of PLAG1 deficiency in knock-out and heterozygous mice compared to wild-type mice using RNA-seq; and (iii) morphological and functional consequences of PLAG1 deficiency by determining testicular histology, daily sperm production and sperm motility in knock-out and wild-type mice. PLAG1 was sparsely expressed in germ cells and in Sertoli cells. Genes known to be involved in spermatogenesis were downregulated in the testes of knock-out mice, as well as Hsd17b3, which encodes a key enzyme in androgen biosynthesis. In the absence of Plag1, a number of genes involved in immune processes and epididymis-specific genes were upregulated in the testes. Finally, loss of PLAG1 resulted in significantly lowered daily sperm production, in reduced sperm motility, and in several animals, in sloughing of the germinal epithelium. Our results demonstrate that the subfertility seen in male PLAG1-deficient mice is, at least in part, the result of significantly reduced sperm output and sperm motility.

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

Improved starch digestion of sucrase deficient shrews treated with oral glucoamylase enzyme supplements

USDA-ARS?s Scientific Manuscript database

Although named because of its sucrose hydrolytic activity, this mucosal enzyme plays a leading role in starch digestion because of its maltase and glucoamylase activities. Sucrase deficient mutant shrews, Suncus murinus, were used as a model to investigate starch digestion in patients with Congenita...

Morpho-physiological parameters affecting iron deficiency chlorosis response in soybean (Glycine max L.)

USDA-ARS?s Scientific Manuscript database

Iron deficiency chlorosis (IDC) leads to severe leaf chlorosis, low photosynthetic rates, and yield reductions of several million metric tons each year. In order to devise breeding and genetic transformation programs that aim at generating high-yielding and IDC-tolerant soybean lines, it is necessar...

Role of vitamin D deficiency in systemic lupus erythematosus incidence and aggravation.

PubMed

Hassanalilou, Tohid; Khalili, Leila; Ghavamzadeh, Saeid; Shokri, Ali; Payahoo, Laleh; Bishak, Yaser Khaje

2017-12-26

Vitamin D is one of the main groups of sterols; playing an important role in phospho-calcic metabolism. The conversion of 7-dehydrocholesterol to pre- vitamin D3 in the skin, through solar ultraviolet B radiation, is the main source of vitamin D. Since lupus patients are usually photosensitive, the risk of developing vitamin D deficiency in is high in this population. Although evidences showed the connotation between systemic lupus erythematosus (SLE) and vitamin D through which SLE can lead to lower vitamin D levels, it is also important to consider the possibility that vitamin D deficiency may have a causative role in SLE etiology. This paper analyzes existing data from various studies to highlight the role of vitamin D deficiency in SLE occurrence and aggravation and the probable efficacy of vitamin D supplementation on SLE patients. We searched "Science Direct" and "Pub Med" using "Vitamin D" and "SLE" for finding the studies focusing on the association between vitamin D deficiency and SLE incidence and consequences. Evidences show that vitamin D plays an important role in the pathogenesis and progression of SLE and vitamin D supplementation seems to ameliorate inflammatory and hemostatic markers; so, can improve clinical subsequent.

Ischaemic Priapism and Glucose-6-Phosphate Dehydrogenase Deficiency: A Mechanism of Increased Oxidative Stress?

PubMed

Morrison, B F; Thompson, E B; Shah, S D; Wharfe, G H

2014-07-03

Ischaemic priapism is a devastating urological condition that has the potential to cause permanent erectile dysfunction. The disorder has been associated with numerous medical conditions and the use of pharmacotherapeutic agents. The aetiology is idiopathic in a number of cases. There are two prior case reports of the association of ischaemic priapism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report on a third case of priapism associated with G6PD deficiency and review recently described molecular mechanisms of increased oxidative stress in the pathophysiology of ischaemic priapism. The case report of a 32-year old Afro-Caribbean male with his first episode of major ischaemic priapism is described. Screening for common causes of ischaemic priapism, including sickle cell disease was negative. Glucose-6-phosphate dehydrogenase deficiency was discovered on evaluation for priapism. Penile aspiration was performed and erectile function was good post treatment.Glucose-6-phosphate dehydrogenase deficiency is a cause for ischaemic priapism and should be a part of the screening process in idiopathic causes of the disorder. Increased oxidative stress occurs in G6PD deficiency and may lead to priapism.

Betaine Deficiency in Maize 1

PubMed Central

Lerma, Claudia; Rich, Patrick J.; Ju, Grace C.; Yang, Wen-Ju; Hanson, Andrew D.; Rhodes, David

1991-01-01

Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency (D Rhodes, PJ Rich [1988] Plant Physiol 88: 102-108). This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline → betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde. PMID:16668098

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

Anemia, Iron Deficiency and Iodine Deficiency among Nepalese School Children.

PubMed

Khatiwada, Saroj; Lamsal, Madhab; Gelal, Basanta; Gautam, Sharad; Nepal, Ashwini Kumar; Brodie, David; Baral, Nirmal

2016-07-01

To assess iodine and iron nutritional status among Nepalese school children. A cross-sectional, community based study was conducted in the two districts, Ilam (hilly region) and Udayapur (plain region) of eastern Nepal. A total of 759 school children aged 6-13 y from different schools within the study areas were randomly enrolled. A total of 759 urine samples and 316 blood samples were collected. Blood hemoglobin level, serum iron, total iron binding capacity and urinary iodine concentration was measured. Percentage of transferrin saturation was calculated using serum iron and total iron binding capacity values. The mean level of hemoglobin, serum iron, total iron binding capacity, transferrin saturation and median urinary iodine excretion were 12.29 ± 1.85 g/dl, 70.45 ± 34.46 μg/dl, 386.48 ± 62.48 μg/dl, 19.94 ± 12.07 % and 274.67 μg/L respectively. Anemia, iron deficiency and iodine deficiency (urinary iodine excretion <100 μg/L) were present in 34.5 %, 43.4 % and 12.6 % children respectively. Insufficient urinary iodine excretion (urinary iodine excretion <100 μg/L) was common in anemic and iron deficient children. Iron deficiency and anemia are common in Nepalese children, whereas, iodine nutrition is more than adequate. Low urinary iodine excretion was common in iron deficiency and anemia.

Evaluation of the humoral immune response of children with low level lead exposure

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

Reigart, J.R.; Graber, C.D.

1976-07-01

Twelve lead-exposed children, with evidence of metabolic impairment, and seven non-lead exposed children were examined for evidence of impairment of their immunological response. There were no differences between the control group and the lead exposed group with reference to complement levels, immunoglobulins, or anamnestic response to the tetanus toxoid antigen. It remains to be demonstrated whether or not there is deficient response to primary immunization, whether other antigens are more affected by lead, or whether impairment of humoral immune response requires a more serious degree of lead intoxication.

Morphological changes in the tracheal epithelium of guinea pigs in conditions of "marginal" vitamin A deficiency. A light, scanning- and transmission-electron microscopic study under special breeding conditions appropriate to early vitamin A deficiency.

PubMed

Stofft, E; Biesalski, H K; Zschaebitz, A; Weiser, H

1992-01-01

The aim of the study was to find out the influence of marginal vitamin A deficiency on morphological structures in the tracheobronchial epithelium in guinea pigs. The tracheobronchial epithelium of animals with vitamin A deficiency (n = 15) and control animals (n = 7), kept under optimal laboratory conditions, was evaluated by light and electron microscopy. The cellular ultrastructure was morphometrically analyzed. The height of the respiratory epithelium was slightly increased. The basal cells were arranged in a loose cell band of three to four layers. The quantity of cytofilaments in their cytoplasm was enhanced. Goblet cells were significantly reduced in vitamin A deficiency. There was also a significant decrease in their secretory granules. The number of ciliated cells was almost unchanged. They showed a significant reduction in mitochondria. The kinocilia often contained an atypical structure of the microtubules. Our findings confirm multiple ultrastructural dysplasias in early vitamin A deficiency which may lead to a disturbance of mucociliary clearance.

DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.

PubMed

Lans, H; Lindvall, J M; Thijssen, K; Karambelas, A E; Cupac, D; Fensgård, O; Jansen, G; Hoeijmakers, J H J; Nilsen, H; Vermeulen, W

2013-12-01

Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.

Metabolic control of respiratory levels in coenzyme Q biosynthesis-deficient Escherichia coli strains leading to fine-tune aerobic lactate fermentation.

PubMed

Wu, Hui; Bennett, George N; San, Ka-Yiu

2015-08-01

A novel strategy to finely control the electron transfer chain (ETC) activity of Escherichia coli was established. In this study, the fine-tuning of the ubiquinone biosynthesis pathway was applied to further controlling ETC function in coenzyme Q8 biosynthesis-deficient E. coli strains, HW108 and HW109, which contain mutations in ubiE and ubiG, respectively. A competing pathway on the intermediate substrates of the Q8 synthesis pathway, catalyzed by diphosphate:4-hydroxybenzoate geranyltransferase (PGT-1) of Lithospermum erythrorhizon, was introduced into these mutant strains. A nearly theoretical yield of lactate production can be achieved under fully aerobic conditions via an in vivo, genetically fine-tunable means to further control the activity of the ETC of the Q8 biosynthesis-deficient E. coli strains. © 2015 Wiley Periodicals, Inc.

[Iron deficiency and pica].

PubMed

Muñoz, J A; Marcos, J; Risueño, C E; de Cos, C; López, R; Capote, F J; Martín, M V; Gil, J L

1998-02-01

To study the relationship between pica and iron-lack anaemia in a series of iron-deficiency patients in order to establish the pathogenesis of such relationship. Four-hundred and thirty-three patients were analysed. Pica was studied by introducing certain diet queries into the clinical history. All patients received oral iron and were periodically controlled with the usual clinico-haematological procedures. Pica was present in 23 patients (5.3%). Eight nourishing (namely, coffee grains, almonds, chocolate, ice, lettuce, carrots, sunflower seeds and bread) and 2 non-nourishing (clay and paper) substances were involved. A second episode of pica appeared in 9 cases upon relapsing of iron deficiency. Both anaemia and pica were cured by etiologic and substitutive therapy in all instances. No clear correlation was found with either socio-economic status or pathogenetic causes of iron deficiency and pica, and no haematological differences were seen between patients with pica and those without this alteration. (1) The pathogenesis of pica is unclear, although it appears unrelated to the degree of iron deficiency. (2) According to the findings in this series, pica seems a consequence of iron deficiency rather than its cause. (3) Adequate therapy can cure both conditions, although pica may reappear upon relapse of iron deficiency.

[Effect of Acaí (Euterpe oleracea) on biological expression characteristics of deficiency-heat and deficiency-cold rats].

PubMed

Wang, Lin-Yuan; Zhang, Jian-Jun; Wang, Chun; Zhu, Ying-Li; Wang, Zi-Chen; He, Cheng; Qu, Yan; Wang, Sha

2016-10-01

To study the effects of Acaí on biological expression characteristics in rats with deficiency-heat and deficiency-cold syndromes, SD rats were divided into blank group, deficiency-heat model group, deficiency-heat+Phellodendri Chinensis Cortex group, deficiency-heat+Acaí high dose and low dose groups, deficiency-cold model group, deficiency-cold+Cinnamomi Cortex group, deficiency-cold+Acaí high dose and low dose groups. The rats were treated with intramuscular injection of hydrocortisone (20 mg•kg⁻¹) or dexamethasone sodium phosphate (0.35 mg•kg⁻¹) for 21 days to set up deficiency-heat model and deficiency-cold models. The levels of cAMP, cGMP, T3, T4 and rT3 were detected by radioimmunoassay. The levels of TP, UA, TC, TG and ALB were detected by colorimetry. The level of cAMP, cAMP/cGMP in serum were reduced in Acaí high dose group (P<0.05, P<0.001). The levels of T3, T4 and rT3 were significantly reduced in the Acaí high dose group (P<0.01, P<0.001, P<0.05). The levels of TP, UA, TC, TG and ALB were significantly reduced in the Acaí high dose group (P<0.001, P<0.05, P<0.05, P<0.05, P<0.01). However, Acaí had no obvious effects on deficiency-cold models. Acaí showed the same effect with Phellodendri Chinensis Cortex in adjusting the levels of deficiency-heat rats; but unlike Cinnamomi Cortex, Acaí showed no obvious effects in adjusting the levels of deficiency-cold rats. Copyright© by the Chinese Pharmaceutical Association.

Iron deficiency anaemia.

PubMed

Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

2016-02-27

Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Glucose-6-phosphate dehydrogenase deficiency

MedlinePlus

G6PD deficiency; Hemolytic anemia due to G6PD deficiency; Anemia - hemolytic due to G6PD deficiency ... Gallagher PG. Hemolytic anemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 161. Janz ...

Calcium Currents of Olfactory Bulb Juxtaglomerular Cells: Profile and Multiple Conductance Plateau Potential Simulation

PubMed Central

Masurkar, Arjun V.; Chen, Wei R.

2011-01-01

The olfactory glomerulus is the locus of information transfer between olfactory sensory neurons and output neurons of the olfactory bulb. Juxtaglomerular cells (JGCs) may influence intraglomerular processing by firing plateau potentials that support multiple spikes. It is unclear what inward currents mediate this firing pattern. In previous work, we characterized potassium currents of JGCs. We focus here on the inward currents using whole cell current clamp and voltage recording in a rat in vitro slice preparation, as well as computer simulation. We first showed that sodium current was not required to mediate plateau potentials. Voltage clamp characterization of calcium current (ICa) determined that ICa consisted of a slow activating, rapidly inactivating (τ10%–90% rise 6–8ms, τinactivation 38–77ms) component Icat1, similar to T-type currents, and a sustained (τinactivation≫500ms) component Icat2, likely composed of L-type and P/Q-type currents. We used computer simulation to test their roles in plateau potential firing. We robustly modeled Icat1 and Icat2 to Hodgkin-Huxley schemes (m3h and m2, respectively) and simulated a JGC plateau potential with 6 conductances: calcium currents as above, potassium currents from our prior study (A-type Ikt1, D-type Ikt2, delayed rectifier Ikt3), and a fast sodium current (INa). We demonstrated that Icat1 was required for mediating the plateau potential, unlike INa and Icat2, and its τinactivation determined plateau duration. We also found that Ikt1 dictated plateau potential shape more than Ikt2 and Ikt3. The influence of these two transient and opposing conductances suggests a unique mechanism of plateau potential physiology. PMID:21704681

Congenital rickets due to vitamin D deficiency in the mothers.

PubMed

Paterson, Colin R; Ayoub, David

2015-10-01

We wished to review all published reports of congenital rickets to identify the causes and characteristics. 25 cases were identified in 19 published reports in which there was radiological and/or histological evidence of rickets in the first two weeks after birth. Cases of rickets associated with maternal renal failure were excluded as were infants born at less than 32 weeks gestation. There was evidence of maternal deficiency in 24 of these cases. In 16 cases the diagnosis of the rickets led to the identification of symptomatic osteomalacia in the mothers. Of the 12 mothers who had assays for serum 25-hydroxyvitamin D (25OHD) 11 had values less than 10 ng/mL. Presentations in the infants included craniotabes, wide skull sutures, rachitic rosaries, enlargement of the wrists, tetany and convulsions. In two cases rickets had been suspected from antenatal X-rays. In five cases fractures were found at the time of initial presentation. Of the 16 infants with serum calcium assays 15 had values lower than 8.8 mg/dL. Of 13 infants who had serum alkaline phosphatase assays 12 had abnormally high levels. Of the seven infants in whom serum 25OHD was measured before treatment, all had values less than 10 ng/mL. These reports provide strong support for the view that maternal deficiency leads to overt bone disease from before birth. Maternal deficiency probably also leads to impairment of bone quality in postnatal life. The importance of ensuring adequate vitamin D nutrition in pregnancy is emphasised. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

PubMed

Kurosawa, Yuko; Degrauw, Ton J; Lindquist, Diana M; Blanco, Victor M; Pyne-Geithman, Gail J; Daikoku, Takiko; Chambers, James B; Benoit, Stephen C; Clark, Joseph F

2012-08-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Vitamin D levels and deficiency with different occupations: a systematic review.

PubMed

Sowah, Daniel; Fan, Xiangning; Dennett, Liz; Hagtvedt, Reidar; Straube, Sebastian

2017-06-22

Vitamin D deficiency is prevalent worldwide, but some groups are at greater risk. We aim to evaluate vitamin D levels in different occupations and identify groups vulnerable to vitamin D deficiency. An electronic search conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and CINAHL Plus with Full Text generated 2505 hits; 71 peer-reviewed articles fulfilled the inclusion criteria. Occupations investigated included outdoor and indoor workers, shiftworkers, lead/smelter workers, coalminers, and healthcare professionals. We calculated the pooled average metabolite level as mean ± SD; deficiency/insufficiency status was described as % of the total number of subjects in a given category. Compared to outdoor workers, indoor workers had lower 25-hydroxyvitamin D (25-(OH)D) levels (40.6 ± 13.3 vs. 66.7 ± 16.7 nmol/L; p < 0.0001). Mean 25-(OH)D levels (in nmol/L) in shiftworkers, lead/smelter workers and coalminers were 33.8 ± 10.0, 77.8 ± 5.4 and 56.6 ± 28.4, respectively. Vitamin D deficiency (25-(OH)D < 50 nmol/L), was high in shiftworkers (80%) and indoor workers (78%) compared to outdoor workers (48%). Among healthcare professionals, medical residents and healthcare students had the lowest levels of mean 25-(OH)D, 44.0 ± 8.3 nmol/L and 45.2 ± 5.5 nmol/L, respectively. The mean 25-(OH)D level of practising physicians, 55.0 ± 5.8 nmol/L, was significantly different from both medical residents (p < 0.0001) and healthcare students (p < 0.0001). Nurses and other healthcare employees had 25-(OH)D levels of 63.4 ± 4.2 nmol/L and 63.0 ± 11.0 nmol/L, respectively, which differed significantly compared to practising physicians (p = 0.01), medical residents (p < 0.0001) and healthcare students (p < 0.0001). Rates of vitamin D deficiency among healthcare professionals were: healthcare students 72%, medical residents 65%, practising physicians 46%, other healthcare employees 44%, and nurses 43

Cerebral Folate Deficiency

ERIC Educational Resources Information Center

Gordon, Neil

2009-01-01

Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

Rare case of eosinophilic granulomatosis with polyangiitis in two patients with α-1-antitrypsin deficiency (PiSZ)

PubMed Central

Moxey, Jordan Maureen; Low, Emma Victoria; Turner, Alice Margaret

2016-01-01

We present two cases of eosinophilic granulomatosis with polyangiitis occurring with α-1-antitrypsin deficiency, both PiSZ phenotype. The simultaneous occurrence of these two conditions has seldom been described in the literature, despite evidence of an association between α-1-antitrypsin deficiency and other forms of vasculitis. Both patients had pulmonary involvement and reported intermittent exacerbations of vasculitic symptoms. Both patients were managed on low-dose oral steroids and azathioprine remaining well with occasional exacerbations. It is important to consider whether there is an association between eosinophilic granulomatosis with polyangiitis and α-1-antitrypsin deficiency, as this may lead to more severe pulmonary symptoms during exacerbations. If a genetic association between the two conditions is found, clinicians should be aware of the possible need to screen for α-1-antitrypsin deficiency in appropriate patients. PMID:27118743

Deficiency of adenosine kinase activity affects the degree of pectin methyl-esterification in cell walls of Arabidopsis thaliana.

PubMed

Pereira, L A R; Schoor, S; Goubet, F; Dupree, P; Moffatt, B A

2006-11-01

Pectin methyl-esterification is catalysed by S-adenosyl-L: -methionine (SAM)-dependent methyltransferases. As deficiency in adenosine kinase (ADK; EC 2.7.1.20) activity impairs SAM recycling and utilization, we investigated the relationship between ADK-deficiency and the degree of pectin methyl-esterification in cell walls of Arabidopsis thaliana. The distribution patterns of epitopes associated with methyl-esterified homogalacturonan in leaves and hypocotyls of wild-type (WT) and ADK-deficient plants were examined using immunolocalization and biochemical techniques. JIM5 and LM7 epitopes, characteristic of low esterified pectins, were more irregularly distributed along the cell wall in ADK-deficient plants than in WT cell walls. In addition, epitopes recognized by JIM7, characteristic of pectins with a higher degree of methyl-esterification, were less abundant in ADK-deficient leaves and hypocotyls. Since de-esterified pectins have enhanced adhesion properties, we propose that the higher abundance and the altered distribution of low methyl-esterified pectin in ADK-deficient cell walls lead to the leaf shape abnormalities observed in these plants.

[Hygienic characteristics of the population's morbidity rate associated with iodine deficiency in the Republic of Mordovia].

PubMed

Blinov, D S; Chemova, N N; Balykova, O P; Liapina, S A; Chugunova, L A

2015-01-01

In the article there are presented the results of research on naturally conditioned insufficiency of trace elements, particularly iodine, in the Republic of Mordovia. Iodine deficiency disorders are referred to the most common non-infectious human pathology. According to WHO data, about two billion people on Earth live in conditions of in iodine deficiency. In the Russian Federation there are no areas in which the population would not be at risk for the development of iodine deficiency disorders. To these regions and the Republic of Mordovia is referred. The prevalence of diseases caused by iodine deficiency among the urban population accounted for 100-150, among rural--130-350. In some regions of endemic goiter rate reaches 800. Analysis of the morbidity rate of the population in the Republic of Mordovia, associated with the iodine deficiency, shows that in the structure of diseases related to micronutrient deficiency, by 2013 diffuse goiter plays a leading role, beingfollowed by a multi-node (endemic) goiter onward thyroiditis, subclinical hypothyroidism and hyperthyroidism. Thus, the analysis of indices of new cases of diseases associated with the iodine deficiency, allows to make the conclusion that diffuse goiter is the most significant pathology. In the structure of diseases related to the micronutrient deficiency, out of the most frequently detected iodine deficiency disorders, the greatest fraction are diffuse and multinodular goiter. The study was conducted with the support of the project, performed in the framework of the basic part of the State assignment (project 2859) and a RHSF grant.

Molecular characterization of FXI deficiency.

PubMed

Berber, Ergul

2011-02-01

Factor XI (FXI) deficiency is a rare autosomal bleeding disease associated with genetic defects in the FXI gene. It is a heterogeneous disorder with variable tendency in bleeding and variable causative FXI gene mutations. It is characterized as a cross-reacting material-negative (CRM-) FXI deficiency due to decreased FXI levels or cross-reacting material-positive (CRM+) FXI deficiency due to impaired FXI function. Increasing number of mutations has been reported in FXI mutation database, and most of the mutations are affecting serine protease (SP) domain of the protein. Functional characterization for the mutations helps to better understand the molecular basis of FXI deficiency. Prevalence of the disease is higher in certain populations such as Ashkenazi Jews. The purpose of this review is to give an overview of the molecular basis of congenital FXI deficiency.

Effects of manganese deficiency on the microstructure of proximal tibia and OPG/RANKL gene expression in chicks.

PubMed

Liu, Ran; Jin, Cong; Wang, Zhenyong; Wang, Zhaojun; Wang, Jian; Wang, Lin

2015-03-01

Manganese (Mn) deficiency can result in perosis in chicks, but the mechanism of Mn deficiency on tibia development remains poorly understood. Ninety one-day-old Arbor Acres male broiler chickens administered with control diet (60 mg Mn/kg) and Mn-deficient diets (40 mg Mn/kg, 8.7 mg Mn/kg) to investigate the effects of Mn deficiency on morphology of tibia and related signal transduction pathways in broiler chickens. At the age of 42 days, the bone trabecula, damaged osteoblasts and OPG/RANKL mRNA expression levels were investigated by histological assessment, electron microscopic examination and real-time quantitative PCR analysis, respectively. Results of histological observations showed that decreased trabecular thickness, trabecular number and trabecular bone area (%) together with increased trabecular bone separation were involved in perosis induced by Mn deficiency. The most striking ultrastructural modifications involved disruption of nuclear membrane and mitochondria outer membrane, loss of mitochondrion cristae and alteration in endoplasmic reticulum in osteoblasts of the Mn-deficient groups. Likewise, Mn deficiency results in a significant (P < 0.05) decrease in the relative mRNA expression levels of OPG and RANKL with a significantly higher RANKL/OPG ratio (P < 0.05). In conclusion, Mn deficiency can affect the development of tibia in broiler chickens, leading to metaphyseal osteoporosis which may be due to decreased OPG/RANKL mRNA expression.

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game.

PubMed

Bereczky, Zsuzsanna; Kovács, Kitti B; Muszbek, László

2010-12-01

Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play an important role in the regulation of blood coagulation as natural anticoagulants. PC is activated by thrombin and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V. The free form of PS is an important cofactor of APC. Deficiencies in these proteins lead to an increased risk of venous thromboembolism; a few reports have also associated these deficiencies with arterial diseases. The degree of risk and the prevalence of PC and PS deficiency among patients with thrombosis and in those in the general population have been examined by several population studies with conflicting results, primarily due to methodological variability. The molecular genetic background of PC and PS deficiencies is heterogeneous. Most of the mutations cause type I deficiency (quantitative disorder). Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases. The diagnosis of PC and PS deficiencies is challenging; functional tests are influenced by several pre-analytical and analytical factors, and the diagnosis using molecular genetics also has special difficulties. Large gene segment deletions often remain undetected by DNA sequencing methods. The presence of the PS pseudogene makes genetic diagnosis even more complicated.

LEDGF/p75 Deficiency Increases Deletions at the HIV-1 cDNA Ends.

PubMed

Bueno, Murilo T D; Reyes, Daniel; Llano, Manuel

2017-09-15

Processing of unintegrated linear HIV-1 cDNA by the host DNA repair system results in its degradation and/or circularization. As a consequence, deficient viral cDNA integration generally leads to an increase in the levels of HIV-1 cDNA circles containing one or two long terminal repeats (LTRs). Intriguingly, impaired HIV-1 integration in LEDGF/p75-deficient cells does not result in a correspondent increase in viral cDNA circles. We postulate that increased degradation of unintegrated linear viral cDNA in cells lacking the lens epithelium-derived growth factor (LEDGF/p75) account for this inconsistency. To evaluate this hypothesis, we characterized the nucleotide sequence spanning 2-LTR junctions isolated from LEDGF/p75-deficient and control cells. LEDGF/p75 deficiency resulted in a significant increase in the frequency of 2-LTRs harboring large deletions. Of note, these deletions were dependent on the 3' processing activity of integrase and were not originated by aberrant reverse transcription. Our findings suggest a novel role of LEDGF/p75 in protecting the unintegrated 3' processed linear HIV-1 cDNA from exonucleolytic degradation.

Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.

PubMed

Feng, Shufang; Shi, Tianyao; Qiu, Jiangxia; Yang, Haihong; Wu, Yan; Zhou, Wenxia; Wang, Wei; Wu, Haitao

2017-10-01

It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in mature hippocampal neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX) + neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1 -/- mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment. © FASEB.

CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue.

PubMed

Bolus, W Reid; Gutierrez, Dario A; Kennedy, Arion J; Anderson-Baucum, Emily K; Hasty, Alyssa H

2015-10-01

Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2(-/-) AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2(-/-) mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2(-/-) bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2(-/-) mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2(-/-) mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation. © Society for Leukocyte Biology.

CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue

PubMed Central

Bolus, W. Reid; Gutierrez, Dario A.; Kennedy, Arion J.; Anderson-Baucum, Emily K.; Hasty, Alyssa H.

2015-01-01

Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2−/− AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2−/− mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2−/− bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2−/− mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2−/− mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation. PMID:25934927

Ferroelectricity and competing interactions in Ho-deficient non-stoichiometric orthorhombic HoMnO{sub 3}

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

Wang, J. X.; Yan, Z. B.; Xie, Y. L.

2015-05-07

We investigate the consequences of the Ho-deficient non-stoichiometry in orthorhombic HoMnO{sub 3} in terms of microscopic mechanisms for ferroelectricity modulation. It is suggested that the Ho-deficiency (then Mn excess) results in Ho-vacancies and then Mn occupation of the Ho-site with increasing non-stoichiometry. The Ho-deficiency enhances the Mn-Mn symmetric exchange striction by suppressing the independent Ho-Ho interaction, and thus benefits to the induced Ho spin ordering against the independent Ho spin ordering. The symmetric Ho-Mn exchange striction is thus enhanced by this induced Ho spin ordering, leading to remarkably enhanced ferroelectric polarization as observed. This work presents an alternative scheme tomore » modulate the multiferroicity in rare-earth manganites of strong 4f-3d coupling.« less

Vitamin D and vitamin B12 deficiencies are common in patients with midgut carcinoid (SI-NET).

PubMed

Lind, A; Wängberg, B; Ellegård, L

2016-09-01

Patients with small intestinal neuroendocrine tumours (SI-NET) often have diarrhoea from hormonal overproduction, surgery and medical treatment, leading to malabsorption of bile salts, fats, vitamin B12 and fat-souble vitamins. This could lead to malnutrition. We assessed nutritional status in 50 consecutive out patients with disseminated SI-NET, 25 patients in each cohort. The first cohort was descriptive and the second cohort supplemented with vitamin D, B12 and calcium. Vitamin D deficiency was defined as <50 nmol/l. All patients were assessed by clinical chemistry and dual-energy X-ray absorptiometry (DXA) and interviewed about weight changes, appetite, gastrointestinal disorders, sunhabits and the use of supplements. In the first cohort, 29% of the patients were severely and 17% moderately vitamin D deficient. In patients without prior substitution, 32% had subnormal vitamin B12 levels. Seventy-six percent had low bone density. In the second cohort with vitamin and mineral supplementation, none had severe vitamin D deficiency, but 28% had moderate deficiency. No patient had subnormal vitamin B12 levels. Sixty percent had low bone density. The serum levels of vitamin D and B12 were higher and parathyroid hormone (PTH) lower in the second cohort compared with the first cohort (P⩽0,022). Vitamin D and PTH were negatively correlated, r=-30, P=⩽0.036. Low serum levels of vitamin D and vitamin B12, and low bone density are common in patients with disseminated SI-NET. Supplementation of vitamin D, B12 and calcium resulted in higher serum levels of vitamins, lower PTH levels and diminished severe vitamin D deficiency and is thus recommended as standard care.

Developmental vitamin D deficiency and schizophrenia: the role of animal models

PubMed Central

Schoenrock, S. A.; Tarantino, L. M.

2016-01-01

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. PMID:26560996

Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention

PubMed Central

Liskay, R.Michael

2014-01-01

Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitates the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells and subsequently tracks the fates of Apc-deficient intestinal cells. Our results suggest that consistent with Apc being a ‘gatekeeper’, loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. In contrast, Apc loss occurring later in life has minimal consequences, with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell-specific Lgr5-CreER mouse, we generated different sized fields of Apc-deficient crypts via independent recombination events and found that field size correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient occult crypt fission. We found that sulindac treatment started early in life inhibits the morphologically occult spread of Apc-deficient crypts and thus reduces adenoma numbers. Taken together these results suggest that: (i) earlier Apc loss promotes increased crypt fission, (ii) a field of Apc-deficient crypts, which can form via occult crypt fission or independent neighboring events, is an important intermediate between loss of Apc and adenoma formation and (iii) normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention. PMID:23996931

Iron deficiency anaemia: with the conclusion of a need for iron reader

NASA Astrophysics Data System (ADS)

Lim, Wai Feng; Yap, Boon Kar; Lai, Mei I.; Talik, Noorazrina; Nasser, Ammar Ahmed; Al-Haiqi, Ahmed Mubarak Ahmed; Sankar Krishnan, Prajindra

2017-10-01

In our bloodstream, there are plenty of red blood cells (RBC), which function as an important oxygen carrier in our bodies. Each RBC consists of millions of haemoglobin (Hb), which is made up from globin and iron. If any deficiency/malfunction of any globin, it will lead to anaemia as indicated in low Hb level while iron deficiency anaemia (IDA) is anaemic due to the lacking of iron as indicated in low Hb and ferritin levels. IDA affects almost two billion people globally while anaemia without iron deficiency, such as thalassaemia, affects almost 4.5% in Malaysian population. These anaemic conditions have similar clinical symptoms like fatigue, dizziness, in which disturb their cognitive development and productivity in workplace. In areas without proper medical access, many anaemic individuals were misdiagnosed and treated with iron tablets because they were thought to have iron deficiency anaemia due to low Hb content. But, excess iron is toxic to the body. Misdiagnosis can be avoided by iron status assessment. We hereby review the currently available iron status parameters in laboratory and field study with the conclusion of demonstrating the importance of a need for iron reader, in the effort to reduce the prevalence of IDA globally.

Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice.

PubMed

Tsou, Ryan C; Zimmer, Derek J; De Jonghe, Bart C; Bence, Kendra K

2012-09-01

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the negative regulation of leptin and insulin receptor signaling. PTP1B(-/-) mice possess a lean metabolic phenotype attributed at least partially to improved hypothalamic leptin sensitivity. Interestingly, mice lacking both leptin and PTP1B (ob/ob:PTP1B(-/-)) have reduced body weight compared with mice lacking leptin only, suggesting that PTP1B may have important leptin-independent metabolic effects. We generated mice with PTP1B deficiency specifically in leptin receptor (LepRb)-expressing neurons (LepRb-PTP1B(-/-)) and compared them with LepRb-Cre-only wild-type (WT) controls and global PTP1B(-/-) mice. Consistent with PTP1B's role as a negative regulator of leptin signaling, our results show that LepRb-PTP1B(-/-) mice are leptin hypersensitive and have significantly reduced body weight when maintained on chow or high-fat diet (HFD) compared with WT controls. LepRb-PTP1B(-/-) mice have a significant decrease in adiposity on HFD compared with controls. Notably, the extent of attenuated body weight gain on HFD, as well as the extent of leptin hypersensitivity, is similar between LepRb-PTP1B(-/-) mice and global PTP1B(-/-) mice. Overall, these results demonstrate that PTP1B deficiency in LepRb-expressing neurons results in reduced body weight and adiposity compared with WT controls and likely underlies the improved metabolic phenotype of global and brain-specific PTP1B-deficient models. Subtle phenotypic differences between LepRb-PTP1B(-/-) and global PTP1B(-/-) mice, however, suggest that PTP1B independent of leptin signaling may also contribute to energy balance in mice.

Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment

PubMed Central

de la Garza, Rocio G.; Morales-Garza, Luis Alonso; Martin-Estal, Irene; Castilla-Cortazar, Inma

2017-01-01

Cirrhosis represents the final stage of chronic liver damage, which can be due to different factors such as alcohol, metabolic syndrome with liver steatosis, autoimmune diseases, drugs, toxins, and viral infection, among others. Nowadays, cirrhosis is an important health problem and it is an increasing cause of morbidity and mortality, being the 14th most common cause of death worldwide. The physiopathological pathways that lead to fibrosis and finally cirrhosis partly depend on the etiology. Nevertheless, some common features are shared in this complex mechanism. Recently, it has been demonstrated that cirrhosis is a dynamic process that can be altered in order to delay or revert fibrosis. In addition, when cirrhosis has been established, insulin-like growth factor-1 (IGF-1) deficiency or reduced availability is a common condition, independently of the etiology of chronic liver damage that leads to cirrhosis. IGF-1 deprivation seriously contributes to the progressive malnutrition of cirrhotic patient, increasing the vulnerability of the liver to establish an inflammatory and oxidative microenvironment with mitochondrial dysfunction. In this context, IGF-1 deficiency in cirrhotic patients can justify some of the common characteristics of these individuals. Several studies in animals and humans have been done in order to test the replacement of IGF-1 as a possible therapeutic option, with promising results. PMID:28270882

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.

Dual pathology as a result of spinal stenosis and vitamin B12 deficiency.

PubMed

Patel, Mohammed Shakil; Rasul, Zurqa; Sell, Philip

2011-12-01

Vitamin B12 deficiency can confound the clinical assessment of patients presenting with features of spinal disorders. Speciality practice within spinal surgery may lead the clinician to a focus upon spinal explanations for symptoms and that belief may be reinforced by supporting imaging. In the presence of mainly sensory symptoms consideration and exclusion of non surgical causes needs to occur. This study aimed at identifying the prevalence of vitamin B12 deficiency; the presence of dual pathology on imaging performed; the implementation of replacement therapy and their subsequent clinical response as perceived by patients. This was performed through a retrospective review of patients presenting to specialist spine out-patient clinics over a 4-year period via access to pathology reports followed by a telephone survey. 457 patients were investigated of which 8.5% were vitamin B12 deficient. 70% of patients had repeat levels and 31% continued to be deficient. 26% of these patients were not placed on any supplemental therapy. 72% of patients on treatment had self perceived improved outcomes as compared with 55% not on treatment. 73% of patients underwent MRI/CT imaging. 59% of which had evidence of spinal stenosis. In older patients with sensory symptoms, the coexistence of B12 deficiency should be considered. Detection of deficiency with consequent treatment results in better global outcomes than no treatment. Unless the correct blood test is done, the pathology will remain undetected, and patients may continue with their primary symptoms despite high-risk spinal surgical procedures.

Fragile X: leading the way for targeted treatments in autism.

PubMed

Wang, Lulu W; Berry-Kravis, Elizabeth; Hagerman, Randi J

2010-07-01

Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur. (c) 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.

Lower Selenoprotein T Expression and Immune Response in the Immune Organs of Broilers with Exudative Diathesis Due to Selenium Deficiency.

PubMed

Pan, Tingru; Liu, Tianqi; Tan, Siran; Wan, Na; Zhang, Yiming; Li, Shu

2018-04-01

The objective of the present study was to investigate whether dietary selenium (Se) deficiency would affect the expression of selenoprotein T (SelT) and immune response in the immune organs of broilers. Changes in expression of inflammatory cytokines and oxidative stress response caused by Se deficiency can lead to organism damage, which in turn leads to immune response. Sixty (1-day-old) broilers were divided into the control group and Se-deficiency group. Animal models with exudative diathesis were duplicated in the broilers by feeding them Se-deficient diet for 20 days. After the Se-deficient group exhibited symptoms of exudative diathesis, all the broilers were euthanized, and their immune organs were taken for analysis. The tissues including spleen, bursa of Fabricius, and thymus were treated to determine the pathological changes (including microscopic and ultramicroscopic), the messenger RNA (mRNA) expression levels of SelT and its synthetase (SecS and SPS1), cytokine mRNA expression levels, and antioxidant status. The microscopic and ultramicroscopic analyses showed that immune tissues were obviously injured in the Se-deficient group. The mRNA expression of SelT was decreased compared with that in the control group. Meanwhile, the mRNA expression levels of SecS and SPS1 were downregulated. In the Se-deficient group, the mRNA expression levels of IL-1R and IL-1β were higher than those of three control organs. Additionally, the IL-2 and INF-γ mRNA expression levels were lower than those of the control group. The activity of CAT was decreased, and the contents of H 2 O 2 and •OH were increased due to Se deficiency. Pearson method analysis showed that the expression of SelT had a positive correlation with IL-2, INF-γ, SecS, and SPS1 and a negative correlation with IL-1R and IL-1β. In summary, these data indicated that Se-deficient diet decreased the SelT expression and its regulation of oxidative stress, and it inhibited a pleiotropic mechanism of the

Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency

PubMed Central

Argente, Jesús; Flores, Raquel; Gutiérrez-Arumí, Armand; Verma, Bhupendra; Martos-Moreno, Gabriel Á; Cuscó, Ivon; Oghabian, Ali; Chowen, Julie A; Frilander, Mikko J; Pérez-Jurado, Luis A

2014-01-01

The molecular basis of a significant number of cases of isolated growth hormone deficiency remains unknown. We describe three sisters affected with severe isolated growth hormone deficiency and pituitary hypoplasia caused by biallelic mutations in the RNPC3 gene, which codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12-type introns. We found anomalies in U11/U12 di-snRNP formation and in splicing of multiple U12-type introns in patient cells. Defective transcripts include preprohormone convertases SPCS2 and SPCS3 and actin-related ARPC5L genes, which are candidates for the somatotroph-restricted dysfunction. The reported novel mechanism for familial growth hormone deficiency demonstrates that general mRNA processing defects of the minor spliceosome can lead to very narrow tissue-specific consequences. Subject Categories Genetics, Gene Therapy ' Genetic Disease; Metabolism PMID:24480542

Selective IgA Deficiency

MedlinePlus

... immunoglobulins. Videos: Choosing Wisely » Selective IgA Deficiency Treatment & Management The underlying cause for Selective IgA Deficiency is ... the Evidence » Practice Parameter for the Diagnosis and Management of Primary Immunodefiency » 2017 Non-CME Recordings » Vaccination ...

Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice.

PubMed

Babaev, Vladimir R; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F; May, James M

2010-09-01

To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis (an inflammatory condition associated with oxidative stress), 4 combinations of vitamin supplementation (low C/low E, low C/high E, high C/low E, and high C/high E) were studied in atherosclerosis-prone apolipoprotein E-deficient mice also unable to synthesize their own vitamin C (gulonolactone oxidase(-/-)); and to evaluate the effect of a more severe depletion of vitamin C alone in a second experiment using gulonolactone oxidase(-/-) mice carrying the hemizygous deletion of SVCT2 (the vitamin C transporter). After 8 weeks of a high-fat diet (16% lard and 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2- to 3-fold in male mice, although only plaque macrophage content was increased in female mice. A more severe deficiency of vitamin C in gulonolactone oxidase(-/-) mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apolipoprotein E(-/-) mice compared with littermates receiving a diet replete in vitamin C, again most clearly in males. Combined deficiencies of vitamins E and C are required to worsen early atherosclerosis in an apolipoprotein E-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.

Genetics Home Reference: factor V deficiency

MedlinePlus

... Twitter Home Health Conditions Factor V deficiency Factor V deficiency Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Factor V deficiency is a rare bleeding disorder. The signs ...

Genetics Home Reference: protein C deficiency

MedlinePlus

... Twitter Home Health Conditions Protein C deficiency Protein C deficiency Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Protein C deficiency is a disorder that increases the risk ...

Genetics Home Reference: factor X deficiency

MedlinePlus

... Twitter Home Health Conditions Factor X deficiency Factor X deficiency Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Factor X deficiency is a rare bleeding disorder that varies ...

Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy

PubMed Central

clar, julie; Gri, Blandine; Calderaro, Julien; Birling, Marie-Christine; Herault, Yann; Smith, Peter; Mithieux, Gilles; Rajas, Fabienne

2014-01-01

Renal failure is a major complication that arises with aging in glycogen storage disease type 1a and type 1b patients. In the kidneys, glucose-6 phosphatase catalytic subunit (encoded by G6pc) deficiency leads to the accumulation of glycogen; this effect results in marked nephromegaly and progressive glomerular hyperperfusion and hyperfiltration, which precede the development of microalbuminuria and proteinuria. To better understand the end-stage nephropathy in glycogen storage disease type 1a, we generated a novel kidney-specific G6pc knock-out (K-G6pc−/−) mouse, which exhibited normal life expectancy. After 6 months of G6pc deficiency, K-G6pc−/− mice showed glycogen overload leading to nephromegaly and tubular dilation. Moreover, renal accumulation of lipids due to activation of de novo lipogenesis was observed. This led to the activation of the renin-angiotensin system and the development of epithelial-mesenchymal transition process and podocyte injury via transforming growth factor β1 signaling. Thus, K-G6pc−/− mice developed microalbuminuria caused by the impairment of glomerular filtration barrier. In conclusion, renal G6pc deficiency alone is sufficient to induce the development of the early onset nephropathy observed in glycogen storage disease type 1a, independently of the liver disease. K-G6pc−/− mouse model is a unique tool to decipher the molecular mechanisms underlying renal failure and to evaluate potential therapeutic strategies. PMID:24717294

Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond.

PubMed

Erez, Ayelet; Nagamani, Sandesh C Sreenath; Lee, Brendan

2011-02-15

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic

Some aspects of the thermodynamic behaviour of the lead-doped Bi-2223 system

NASA Astrophysics Data System (ADS)

Tetenbaum, M.; Maroni, V. A.

1996-02-01

A thermodynamic assessment of lead-doped Bi-2223 with emphasis on compositions and oxygen partial pressures within the homogeneity region prior to solid-state decomposition is presented. Equations for the variation of oxygen partial pressure with composition and temperature have been derived from our EMF measurements. Long-term metastability was indicated during cycling over a temperature range of ∼ 700-815°C of a lead-doped Bi-2223 sample having an oxygen-deficient stoichiometry of 9.64 prior to solid-state decomposition corresponding to the diphasic CuOCu 2O system. A trend of increasing negative values of the partial molar enthalpy Δ overlineH( O 2) and entropy Δ overlineS( O2 with increasing oxygen deficiency of the condensed phase indicated an increase in ordering of the cuprate structure prior to solid-state decomposition.

Genetics Home Reference: factor VII deficiency

MedlinePlus

... Facebook Twitter Home Health Conditions Factor VII deficiency Factor VII deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Factor VII deficiency is a rare bleeding disorder that varies ...

A Cause of Permanent Ketosis: GLUT-1 Deficiency.

PubMed

Chenouard, Alexis; Vuillaumier-Barrot, Sandrine; Seta, Nathalie; Kuster, Alice

2015-01-01

GLUT-1-deficiency syndrome (GLUT1-DS; OMIM 606777) is a treatable metabolic disorder caused by a mutation of SLC2A1 gene. The functional deficiency of the GLUT1 protein leads to an impaired glucose transport into the brain, resulting in neurologic disorders.We report on a 6-month-old boy with preprandial malaises who was treated monthly by a sorcerer because of a permanent acetonemic odor. He subsequently developed pharmaco-resistant seizures with microcephaly and motor abnormalities. Metabolic explorations were unremarkable except for a fasting glucose test which revealed an abnormal increase of blood ketone bodies. At the age of 35 months, GLUT1-DS was diagnosed based on hypoglycorrhachia with a decreased CSF to blood glucose ratio, and subsequent direct sequencing of the SLC2A1 gene revealed a de novo heterozygous mutation, c.349A>T (p.Lys117X) on exon 4. It was noteworthy that the patient adapted to the deficient cerebral glucose transport by permanent ketone body production since early life. Excessive ketone body production in this patient provided an alternative energy substrate for his brain. We suggest a cerebral metabolic adaptation with upregulation of monocarboxylic acid transporter proteins (MCT1) at the blood-brain barrier provoked by neuroglycopenia and allowing ketone body utilization by the brain. This case illustrates that GLUT1-DS should be considered in the differential diagnosis of permanent ketosis.

Metformin Use Is Not Associated With B12 Deficiency or Neuropathy in Patients With Type 2 Diabetes Mellitus in Qatar.

PubMed

Elhadd, Tarik; Ponirakis, Georgios; Dabbous, Zeinab; Siddique, Mashhood; Chinnaiyan, Subitha; Malik, Rayaz A

2018-01-01

Metformin may lead to B 12 deficiency and neuropathy. There are no published data on the prevalence of Metformin-related B 12 deficiency and neuropathy in the Arabian Gulf. Determine whether Metformin intake is associated with B 12 deficiency and whether B 12 deficiency is associated with diabetic peripheral neuropathy (DPN) and painful diabetic neuropathy. Patients with type 2 diabetes mellitus (T2DM) ( n  = 362) attending outpatient clinics at HMC underwent assessment of B 12 levels, the DN4 questionnaire, and vibration perception threshold (VPT). Comparing Metformin to non-Metformin users there were no differences in B 12 levels, VPT, or DN4. The prevalence of B 12 deficiency (B 12 <133 pmol/l) was lower ( P  < 0.01) in Metformin (8%) compared to non-Metformin (19%) users. Patients with B 12 deficiency had a comparable prevalence and severity of sensory neuropathy and painful neuropathy to patients without B 12 deficiency. Serum B 12 levels were comparable between Metformin and non-Metformin users with T2DM in Qatar. T2DM patients on Metformin had a lower prevalence of B 12 deficiency. Furthermore, the prevalence and severity of neuropathy and painful diabetic neuropathy were comparable between patients with and without B 12 deficiency.

Review on Vitamin K Deficiency and its Biomarkers: Focus on the Novel Application of PIVKA-II in Clinical Practice.

PubMed

Dong, Rui; Wang, Nianyue; Yang, Yongfeng; Ma, Li; Du, Qiang; Zhang, Wei; Tran, Anh H; Jung, Haiyoung; Soh, Andrew; Zheng, Yijie; Zheng, Shan

2018-04-01

Vitamin K (VK) is a co-factor of the γ-glutamyl carboxylase that catalyzes the conversion of glutamate residues to γ-carboxyglutamate in VK-dependent proteins. The carboxylation reaction imparts the essential calcium-binding residues for the biological function of several proteins involved in the process of coagulation and bone metabolism. VK deficiency is frequently encountered in newborns and can lead to fatal hemorrhagic complications. This review describes and discusses the clinical application of VK deficiency testing. References and data were researched in PubMed and reviewed. In adults, VK deficiency is associated with uncontrolled bleeding, liver dysfunction, osteoporosis, and coronary diseases. An improved understanding of the role of VK deficiency in health and illness can be achieved by setting a gold-standard in the inter-laboratory estimations of VK. However, conventional methods used to measure the VK deficiency based upon the coagulation time lack sensitivity and specificity. Recently, the alterations in proteins induced by VK absence or antagonism (PIVKA) have proven to be suitable biomarkers for detecting VK deficiency. The measurement of PIVKA-II exhibits an enhanced sensitivity and specificity in comparison to other methods conventionally used for the assessment of VK deficiency in newborns and adults. PIVKA-II could potentially be employed as an effective biomarker in the diagnosis of VK deficiency.

PATHOGENESIS OF THE OCULAR LESIONS PRODUCED BY A DEFICIENCY OF VITAMINE A

PubMed Central

Yudkin, Arthur M.; Lambert, Robert A.

1923-01-01

The earliest lesions in ophthalmia of rats resulting from a deficiency of vitamine A consist in focal inflammatory lesions in the conjunctivæ of the lids and nictitating membrane. The involvement of the cornea, which constitutes the most conspicuous feature of the well developed ophthalmia, is a secondary phenomenon. The characteristic corneal plaque consists of keratinized epithelium beneath which the deeper layers of epithelium are generally found intact. Pathologically, the ocular manifestations of a deficiency of vitamine A are referable to a low grade inflammatory process, originating in the palpebral conjunctiva and spreading to the cornea. The rapidity of development and the degree of destruction probably depend in large part on the type of bacterial infection. The specific changes which lead to the establishment of such an infection have not been determined. It is conceivable that they may be either physiological or anatomical. There is some evidence in favor of a general disturbance of antibody formation in animals on deficient diets. The possibility of a disturbed function in the paraocular glands must be considered. PMID:19868767

Replication Protein A (RPA) deficiency activates the Fanconi anemia DNA repair pathway.

PubMed

Jang, Seok-Won; Jung, Jin Ki; Kim, Jung Min

2016-09-01

The Fanconi anemia (FA) pathway regulates DNA inter-strand crosslink (ICL) repair. Despite our greater understanding of the role of FA in ICL repair, its function in the preventing spontaneous genome instability is not well understood. Here, we show that depletion of replication protein A (RPA) activates the FA pathway. RPA1 deficiency increases chromatin recruitment of FA core complex, leading to FANCD2 monoubiquitination (FANCD2-Ub) and foci formation in the absence of DNA damaging agents. Importantly, ATR depletion, but not ATM, abolished RPA1 depletion-induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub. Interestingly, we found that depletion of hSSB1/2-INTS3, a single-stranded DNA-binding protein complex, induces FANCD2-Ub, like RPA1 depletion. More interestingly, depletion of either RPA1 or INTS3 caused increased accumulation of DNA damage in FA pathway deficient cell lines. Taken together, these results indicate that RPA deficiency induces activation of the FA pathway in an ATR-dependent manner, which may play a role in the genome maintenance.

Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation.

PubMed

Marcadier, Julien L; Boland, Margaret; Scott, C Ronald; Issa, Kheirie; Wu, Zaining; McIntyre, Adam D; Hegele, Robert A; Geraghty, Michael T; Lines, Matthew A

2015-02-03

Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea. © 2015 Canadian Medical Association or its licensors.

Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency.

PubMed

Gul, Ersin; Sayar, Esra Hazar; Gungor, Bilgi; Eroglu, Fehime Kara; Surucu, Naz; Keles, Sevgi; Guner, Sukru Nail; Findik, Siddika; Alpdundar, Esin; Ayanoglu, Ihsan Cihan; Kayaoglu, Basak; Geckin, Busra Nur; Sanli, Hatice Asena; Kahraman, Tamer; Yakicier, Cengiz; Muftuoglu, Meltem; Oguz, Berna; Cagdas Ayvaz, Deniz Nazire; Gursel, Ihsan; Ozen, Seza; Reisli, Ismail; Gursel, Mayda

2017-11-16

Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

Clinical significance of enzymatic deficiencies in the gastrointestinal tract with particular reference to lactase deficiency.

PubMed

Rossi, E; Lentze, M J

1984-12-01

The study of deficiencies of small intestinal brush-border hydrolases increased our knowledge about the specific functions of hydrolases in the digestion of smaller molecules on the microvillus surface of the absorptive cells. The sucrase-isomaltase (SI) complex has been shown to be synthesized as a precursor (pro-sucrase-isomaltase) which is then incorporated into the membrane. The hydrophobic N-terminal end of the molecule is anchored in the lipid bilayer. In SI deficiency the molecular base of the disease is still not clear. Absence of SI activity could be due to complete lack of precursor synthesis or to structural changes within the N-terminal end of the SI-complex. Deficiencies of peptide hydrolases have not been reported with the exception of enteropeptidase (EP). Here a congenital deficiency of the enzyme was observed as the primary defect in enzyme synthesis within the enterocytes and as a secondary defect due to exocrine pancreatic insufficiency. In contrast to the primary EP deficiency, the activity of EP can be restored in the cases of exocrine pancreatic insufficiency by treatment with pancreatic extracts. Primary lactase deficiency exists in various forms. Besides congenital lactase deficiency, the late onset or adult type of lactase deficiency has been observed. The latter occurs in many different ethnic groups around the world. Here, using gel electrophoresis and immunoelectrophoresis, the lack of enzyme activity could be shown to be a primary defect in enzyme protein synthesis. In man and in the rat, two different lactases have been identified. In contrast to adult lactase, fetal lactase contains sialic acid at the end of carbohydrate side chains.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined Vitamin C and Vitamin E Deficiency Worsens Early Atherosclerosis in ApoE-Deficient Mice

PubMed Central

Babaev, Vladimir R.; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F.; May, James M.

2010-01-01

Objective Atherosclerosis is an inflammatory condition associated with oxidative stress, but controversy persists regarding whether antioxidants such as vitamins C and E are preventative. To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis, four combinations of vitamin supplementation (Low C/Low E, Low C/High E, High C/Low E, High C/High E) were studied in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice also unable to synthesize their own vitamin C (gulo−/−). The effect of a more severe depletion of vitamin C alone was evaluated in a second experiment using gulo−/− mice carrying the hemizygous deletion of SVCT2, the vitamin C transporter. Methods and Results After 8 weeks on a high-fat diet (16% lard, 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2-3-fold in males, although only plaque macrophage content was increased in females. A more severe deficiency of vitamin C in gulo−/− mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apoE−/− mice compared to littermates on a diet replete in vitamin C, again most clearly in males. Conclusion Combined vitamin E and C deficiencies are required to worsen early atherosclerosis in an apoE-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete. PMID:20558818

Colon and Endometrial Cancers with Mismatch Repair Deficiency can Arise from Somatic, Rather Than Germline, Mutations

PubMed Central

Haraldsdottir, Sigurdis; Hampel, Heather; Tomsic, Jerneja; Frankel, Wendy L.; Pearlman, Rachel; de la Chapelle, Albert; Pritchard, Colin C.

2014-01-01

Background & Aims Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the MMR proteins MLH1, MSH2, MSH6 and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. Methods We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE and POLD1 with ColoSeq and mutation frequencies were established. Results Twenty-two of 32 patients (69%) were found to have two somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 tumors without somatic mutations in MMR genes, 3 had somatic mutations with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had no mutations known to be associated with MMR deficiency. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/Mb); 6 had mutation frequencies >200 per Mb, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase. Conclusions Some patients are found to have tumors with MMR deficiency during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to

Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition

PubMed Central

Stoffel, Wilhelm; Hammels, Ina; Jenke, Bitta; Binczek, Erika; Schmidt-Soltau, Inga; Brodesser, Susanne; Schauss, Astrid; Etich, Julia; Heilig, Juliane; Zaucke, Frank

2016-01-01

Systemic loss of neutral sphingomyelinase (SMPD3) in mice leads to a novel form of systemic, juvenile hypoplasia (dwarfism). SMPD3 deficiency in mainly two growth regulating cell types contributes to the phenotype, in chondrocytes of skeletal growth zones to skeletal malformation and chondrodysplasia, and in hypothalamic neurosecretory neurons to systemic hypothalamus–pituitary–somatotropic hypoplasia. The unbiased smpd3−/− mouse mutant and derived smpd3−/− primary chondrocytes were instrumental in defining the enigmatic role underlying the systemic and cell autonomous role of SMPD3 in the Golgi compartment. Here we describe the unprecedented role of SMPD3. SMPD3 deficiency disrupts homeostasis of sphingomyelin (SM), ceramide (Cer) and diacylglycerol (DAG) in the Golgi SMPD3-SMS1 (SM-synthase1) cycle. Cer and DAG, two fusogenic intermediates, modify the membrane lipid bilayer for the initiation of vesicle formation and transport. Dysproteostasis, unfolded protein response, endoplasmic reticulum stress and apoptosis perturb the Golgi secretory pathway in the smpd3−/− mouse. Secretion of extracellular matrix proteins is arrested in chondrocytes and causes skeletal malformation and chondrodysplasia. Similarly, retarded secretion of proteo-hormones in hypothalamic neurosecretory neurons leads to hypothalamus induced combined pituitary hormone deficiency. SMPD3 in the regulation of the protein vesicular secretory pathway may become a diagnostic target in the etiology of unknown forms of juvenile growth and developmental inhibition. PMID:27882938

Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition.

PubMed

Stoffel, Wilhelm; Hammels, Ina; Jenke, Bitta; Binczek, Erika; Schmidt-Soltau, Inga; Brodesser, Susanne; Schauss, Astrid; Etich, Julia; Heilig, Juliane; Zaucke, Frank

2016-11-24

Systemic loss of neutral sphingomyelinase (SMPD3) in mice leads to a novel form of systemic, juvenile hypoplasia (dwarfism). SMPD3 deficiency in mainly two growth regulating cell types contributes to the phenotype, in chondrocytes of skeletal growth zones to skeletal malformation and chondrodysplasia, and in hypothalamic neurosecretory neurons to systemic hypothalamus-pituitary-somatotropic hypoplasia. The unbiased smpd3-/- mouse mutant and derived smpd3-/- primary chondrocytes were instrumental in defining the enigmatic role underlying the systemic and cell autonomous role of SMPD3 in the Golgi compartment. Here we describe the unprecedented role of SMPD3. SMPD3 deficiency disrupts homeostasis of sphingomyelin (SM), ceramide (Cer) and diacylglycerol (DAG) in the Golgi SMPD3-SMS1 (SM-synthase1) cycle. Cer and DAG, two fusogenic intermediates, modify the membrane lipid bilayer for the initiation of vesicle formation and transport. Dysproteostasis, unfolded protein response, endoplasmic reticulum stress and apoptosis perturb the Golgi secretory pathway in the smpd3-/- mouse. Secretion of extracellular matrix proteins is arrested in chondrocytes and causes skeletal malformation and chondrodysplasia. Similarly, retarded secretion of proteo-hormones in hypothalamic neurosecretory neurons leads to hypothalamus induced combined pituitary hormone deficiency. SMPD3 in the regulation of the protein vesicular secretory pathway may become a diagnostic target in the etiology of unknown forms of juvenile growth and developmental inhibition.

What Is Combined Deficiency of Vitamin K-Dependent Clotting Factors?

MedlinePlus

... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

Latent manganese deficiency increases transpiration in barley (Hordeum vulgare).

PubMed

Hebbern, Christopher A; Laursen, Kristian Holst; Ladegaard, Anne H; Schmidt, Sidsel B; Pedas, Pai; Bruhn, Dan; Schjoerring, Jan K; Wulfsohn, Dvoralai; Husted, Søren

2009-03-01

To investigate if latent manganese (Mn) deficiency leads to increased transpiration, barley plants were grown for 10 weeks in hydroponics with daily additions of Mn in the low nM range. The Mn-starved plants did not exhibit visual leaf symptoms of Mn deficiency, but Chl a fluorescence measurements revealed that the quantum yield efficiency of PSII (F(v)/F(m)) was reduced from 0.83 in Mn-sufficient control plants to below 0.5 in Mn-starved plants. Leaf Mn concentrations declined from 30 to 7 microg Mn g(-1) dry weight in control and Mn-starved plants, respectively. Mn-starved plants had up to four-fold higher transpiration than control plants. Stomatal closure and opening upon light/dark transitions took place at the same rate in both Mn treatments, but the nocturnal leaf conductance for water vapour was still twice as high in Mn-starved plants compared with the control. The observed increase in transpiration was substantiated by (13)C-isotope discrimination analysis and gravimetric measurement of the water consumption, showing significantly lower water use efficiency in Mn-starved plants. The extractable wax content of leaves of Mn-starved plants was approximately 40% lower than that in control plants, and it is concluded that the increased leaf conductance and higher transpirational water loss are correlated with a reduction in the epicuticular wax layer under Mn deficiency.

Activity of xenobiotic-metabolizing enzymes in the liver of rats with multi-vitamin deficiency.

PubMed

Tutelyan, Victor A; Kravchenko, Lidia V; Aksenov, Ilya V; Trusov, Nikita V; Guseva, Galina V; Kodentsova, Vera M; Vrzhesinskaya, Oksana A; Beketova, Nina A

2013-01-01

The purpose of the study was to determine how multi-vitamin deficiency affects xenobiotic-metabolizing enzyme (XME) activities in the rat liver. Vitamin levels and XME activities were studied in the livers of male Wistar rats who were fed for 4 weeks with semi-synthetic diets containing either adequate (100 % of recommended vitamin intake) levels of vitamins (control), or decreased vitamin levels (50 % or 20 % of recommended vitamin intake). The study results have shown that moderate vitamin deficiency (50 %) leads to a decrease of vitamin A levels only, and to a slight increase, as compared with the control, in the following enzyme activities: methoxyresorufin O-dealkylase (MROD) activity of CYP1 A2 - by 34 % (p < 0.05), UDP-glucuronosyl transferase - by 26 % (p < 0.05), and quinone reductase - by 55 % (p < 0.05). Profound vitamin deficiency (20 %) led to a decrease of vitamins A, E, B1, B2, and C, and enzyme activities in the liver: MROD - to 78 % of the control level (p < 0.05), 4-nitrophenol hydroxylase - to 74 % (p < 0.05), heme oxygenase-1 - to 83 % (p < 0.05), and quinone reductase - to 60 % (p < 0.05). At the same time, the UDP-glucuronosyl transferase activity and ethoxyresorufin O-dealkylase activity of CYP1A1, pentoxyresorufin O-dealkylase activity of CYP2B1/2 and 6β-testosterone hydroxylase, as well as the total activity of glutathione transferase did not differ from the control levels. The study has demonstrated that profound multi-vitamin deficiency is associated with a decrease in the expression of CYP1A2 and CYP3A1 mRNAs to 62 % and 79 %, respectively. These data indicated that a short-term but profound multi-vitamin deficiency in rats leads to a decrease in the activities and expression of the some XME that play an important role in detoxification of xenobiotics and metabolism of drugs and antioxidant protection.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

PubMed Central

Kurosawa, Yuko; DeGrauw, Ton J.; Lindquist, Diana M.; Blanco, Victor M.; Pyne-Geithman, Gail J.; Daikoku, Takiko; Chambers, James B.; Benoit, Stephen C.; Clark, Joseph F.

2012-01-01

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8–/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8–/y mouse was comparable to that of human patients. We successfully treated the Slc6a8–/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8–/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8–/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency. PMID:22751104

High predictive value of brain MRI imaging in primary mitochondrial respiratory chain deficiency.

PubMed

de Beaurepaire, Isaure; Grévent, David; Rio, Marlène; Desguerre, Isabelle; de Lonlay, Pascale; Levy, Raphaël; Dangouloff-Ros, Volodia; Bonnefont, Jean-Paul; Barcia, Giulia; Funalot, Benoit; Besmond, Claude; Metodiev, Metodi D; Ruzzenente, Benedetta; Assouline, Zahra; Munnich, Arnold; Rötig, Agnès; Boddaert, Nathalie

2018-06-01

Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies. Starting from a large series of 189 patients (median age: 3.5 years (8 days-56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies. Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum. Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency. © Article author(s) (or their

Anaemia, iron deficiency and iron deficiency anaemia among blood donors in Port Harcourt, Nigeria.

PubMed

Jeremiah, Zaccheaus Awortu; Koate, Baribefe Banavule

2010-04-01

There is paucity of information on the effect of blood donation on iron stores in Port Harcourt, Nigeria. The present study was, therefore, designed to assess, using a combination of haemoglobin and iron status parameters, the development of anaemia and prevalence of iron deficiency anaemia in this area of Nigeria. Three hundred and forty-eight unselected consecutive whole blood donors, comprising 96 regular donors, 156 relatives of patients and 96 voluntary donors, constituted the study population. Three haematological parameters (haemoglobin, packed cell volume, and mean cell haemoglobin concentration) and four biochemical iron parameters (serum ferritin, serum iron, total iron binding capacity and transferrin saturation) were assessed using standard colorimetric and ELISA techniques. The prevalence of anaemia alone (haemoglobin <11.0 g/dL) was 13.7%. The prevalence of isolated iron deficiency (serum ferritin <12 ng/mL) was 20.6% while that of iron-deficiency anaemia (haemoglobin <11.0 g/dL + serum ferritin <12.0 ng/mL) was 12.0%. Among the three categories of the donors, the regular donors were found to be most adversely affected as shown by the reduction in mean values of both haematological and biochemical iron parameters. Interestingly, anaemia, iron deficiency and iron-deficiency anaemia were present almost exclusively among regular blood donors, all of whom were over 35 years old. Anaemia, iron deficiency and iron-deficiency anaemia are highly prevalent among blood donors in Port Harcourt, Nigeria. It will be necessary to review the screening tests for the selection of blood donors and also include serum ferritin measurement for the routine assessment of blood donors, especially among regular blood donors.

Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

PubMed Central

Risson, Valérie; Mazelin, Laetitia; Roceri, Mila; Sanchez, Hervé; Moncollin, Vincent; Corneloup, Claudine; Richard-Bulteau, Hélène; Vignaud, Alban; Baas, Dominique; Defour, Aurélia; Freyssenet, Damien; Tanti, Jean-François; Le-Marchand-Brustel, Yannick; Ferrier, Bernard; Conjard-Duplany, Agnès; Romanino, Klaas; Bauché, Stéphanie; Hantaï, Daniel; Mueller, Matthias; Kozma, Sara C.; Thomas, George; Rüegg, Markus A.; Ferry, Arnaud; Pende, Mario; Bigard, Xavier; Koulmann, Nathalie

2009-01-01

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent. PMID:20008564

Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis

PubMed Central

Ferriero, Rosa; Manco, Giuseppe; Lamantea, Eleonora; Nusco, Edoardo; Ferrante, Mariella I.; Sordino, Paolo; Stacpoole, Peter W.; Lee, Brendan; Zeviani, Massimo; Brunetti-Pierri, Nicola

2014-01-01

Lactic acidosis is a build-up of lactic acid in the blood and tissues, which can be due to several inborn errors of metabolism as well as nongenetic conditions. Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. Phosphorylation of specific serine residues of the E1α subunit of PDHC by pyruvate dehydrogenase kinase (PDK) inactivates the enzyme, whereas dephosphorylation restores PDHC activity. We found that phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of PDK. Phenylbutyrate given to C57B6/L wild-type mice results in a significant increase in PDHC enzyme activity and a reduction of phosphorylated E1α in brain, muscle, and liver compared to saline-treated mice. By means of recombinant enzymes, we showed that phenylbutyrate prevents phosphorylation of E1α through binding and inhibition of PDK, providing a molecular explanation for the effect of phenylbutyrate on PDHC activity. Phenylbutyrate increases PDHC activity in fibroblasts from PDHC-deficient patients harboring various molecular defects and corrects the morphological, locomotor, and biochemical abnormalities in the noam631 zebrafish model of PDHC deficiency. In mice, phenylbutyrate prevents systemic lactic acidosis induced by partial hepatectomy. Because phenylbutyrate is already approved for human use in other diseases, the findings of this study have the potential to be rapidly translated for treatment of patients with PDHC deficiency and other forms of primary and secondary lactic acidosis. PMID:23467562

Glucose-6-phosphate dehydrogenase deficiency (G6PD) as a risk factor of male neonatal sepsis.

PubMed

Rostami-Far, Z; Ghadiri, K; Rostami-Far, M; Shaveisi-Zadeh, F; Amiri, A; Rahimian Zarif, B

2016-01-01

Introduction. Neonatal sepsis is a disease process, which represents the systemic response of bacteria entering the bloodstream during the first 28 days of life. The prevalence of sepsis is higher in male infants than in females, but the exact cause is unknown. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway, which leads to the production of NADPH. NADPH is required for the respiratory burst reaction in white blood cells (WBCs) to destroy microorganisms. The purpose of this study was to evaluate the prevalence of G6PD deficiency in neonates with sepsis. Materials and methods. This study was performed on 76 neonates with sepsis and 1214 normal neonates from February 2012 to November 2014 in the west of Iran. The G6PD deficiency status was determined by fluorescent spot test. WBCs number and neutrophils percentages were measured and compared in patients with and without G6PD deficiency. Results. The prevalence of the G6PD deficiency in neonates with sepsis was significantly higher compared to the control group (p=0.03). WBCs number and neutrophils percentages in G6PD deficient patients compared with patients without G6PD deficiency were decreased, but were not statistically significant (p=0.77 and p=0.86 respectively). Conclusions. G6PD deficiency is a risk factor of neonatal sepsis and also a justification for more male involvement in this disease. Therefore, newborn screening for this disorder is recommended.

Protease-Activated Receptor-2 Deficiency Attenuates Atherosclerotic Lesion Progression and Instability in Apolipoprotein E-Deficient Mice

PubMed Central

Zuo, Pengfei; Zuo, Zhi; Zheng, Yueyue; Wang, Xin; Zhou, Qianxing; Chen, Long; Ma, Genshan

2017-01-01

Inflammatory mechanisms are involved in the process of atherosclerotic plaque formation and rupture. Accumulating evidence suggests that protease-activated receptor (PAR)-2 contributes to the pathophysiology of chronic inflammation on the vasculature. To directly examine the role of PAR-2 in atherosclerosis, we generated apolipoprotein E/PAR-2 double-deficient mice. Mice were fed with high-fat diet for 12 weeks starting at ages of 6 weeks. PAR-2 deficiency attenuated atherosclerotic lesion progression with reduced total lesion area, reduced percentage of stenosis and reduced total necrotic core area. PAR-2 deficiency increased fibrous cap thickness and collagen content of plaque. Moreover, PAR-2 deficiency decreased smooth muscle cell content, macrophage accumulation, matrix metallopeptidase-9 expression and neovascularization in plaque. Relative quantitative PCR assay using thoracic aorta revealed that PAR-2 deficiency reduced mRNA expression of inflammatory molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. In vitro experiment, we found that PAR-2 deficiency reduced mRNA expression of interferon-γ, interleukin-6, TNF-α and MCP-1 in macrophage under unstimulated and lipopolysaccharide-stimulated conditions. These results suggest that PAR-2 deficiency attenuates the progression and instability of atherosclerotic plaque. PMID:28959204

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood

PubMed Central

Wong-Goodrich, Sarah J.E.; Tognoni, Christina M.; Mellott, Tiffany J.; Glenn, Melissa J.; Blusztajn, Jan K.; Williams, Christina L.

2011-01-01

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12–17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. PMID:21840511

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.

PubMed

Andrianova, Maria A; Chetan, Ghati Kasturirangan; Sibin, Madathan Kandi; Mckee, Thomas; Merkler, Doron; Narasinga, Rao Kvl; Ribaux, Pascale; Blouin, Jean-Louis; Makrythanasis, Periklis; Seplyarskiy, Vladimir B; Antonarakis, Stylianos E; Nikolaev, Sergey I

2017-11-01

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo - , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo - disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

OsPRX2 contributes to stomatal closure and improves potassium deficiency tolerance in rice.

PubMed

Mao, Xiaohui; Zheng, Yanmei; Xiao, Kaizhuan; Wei, Yidong; Zhu, Yongsheng; Cai, Qiuhua; Chen, Liping; Xie, Huaan; Zhang, Jianfu

2018-01-01

Peroxiredoxins (Prxs) which are thiol-based peroxidases have been implicated in the toxic reduction and intracellular concentration regulation of hydrogen peroxide. In Arabidopsis thaliana At2-CysPrxB (At5g06290) has been demonstrated to be essential in maintaining the water-water cycle for proper H 2 O 2 scavenging. Although the mechanisms of 2-Cys Prxs have been extensively studied in Arabidopsis thaliana, the function of 2-Cys Prxs in rice is unclear. In this study, a rice homologue gene of At2-CysPrxB, OsPRX2 was investigated aiming to characterize the effect of 2-Cys Prxs on the K + -deficiency tolerance in rice. We found that OsPRX2 was localized in the chloroplast. Overexpressed OsPRX2 causes the stomatal closing and K + -deficiency tolerance increasing, while knockout of OsPRX2 lead to serious defects in leaves phenotype and the stomatal opening under the K + -deficiency tolerance. Detection of K + accumulation, antioxidant activity of transgenic plants under the starvation of potassium, further confirmed that OsPRX2 is a potential target for engineering plants with improved potassium deficiency tolerance. Copyright © 2017 Elsevier Inc. All rights reserved.

MENTAL DEFICIENCY. SECOND EDITION.

ERIC Educational Resources Information Center

HILLIARD, L.T.; KIRMAN, BRIAN H.

REVISED TO INCLUDE LEGISLATIVE AND ADMINISTRATIVE PROCEDURES NEW IN BRITAIN SINCE THE 1957 EDITION, THE TEXT INCLUDES RECENT ADVANCES IN ETIOLOGY, PATHOLOGY, AND TREATMENT OF MENTAL DEFICIENCY. CONSIDERATION OF THE BACKGROUND OF MENTAL DEFICIENCY INCLUDES HISTORICAL AND LEGAL ASPECTS, THE SOCIAL BACKGROUND OF MENTAL DEFECT, PRENATAL CAUSES OF…

[Alpha-1 antitrypsin deficiency. The experience of Pulido Valente Hospital with augmentation therapy].

PubMed

Alves Costa, Carla; Santos, Cristina

2009-01-01

Alpha-1 antitrypsin (AAT) is synthesised in the liver and has half-life of 4-5 days. AAT has antiprotease activity, with particular affinity for neutrophil elastase. Its deficiency leads to a lack of effective lung protection against activated neutrophil enzymes. Deficiency of AAT is a genetic disorder that occurs as a result of the inheritance of two protease inhibitor deficient alleles. Of the deficient alleles, Pi*Z is the most common, and the homozygous form Pi*ZZ results in the lowest serum levels, usually below 50 mg/ dl. The "protective threshold" is 80 mg/dl. Smoking increases the risk of emphysema. The current goal of augmentation therapy is to raise the plasma levels, above protective threshold and slow disease progression. The authors present the experience of the Day Care Hospital of the Pulido Valente Hospital with five male patients presenting emphysema due to AAT deficiency, receiving weekly intravenous treatment with Prolastin. We performed a clinical, respiratory functional and radiological evaluation between 2003 and 2007. The results point to a slower progression of the disease, with clinical and radiological stability and a reduced rate of FEV1 decline. Augmentation therapy is an expensive treatment and its use is lacking supportive evidence of efficacy by randomized controlled clinical trials. Evidence that it confers benefits is based on observational studies. Our experience is positive, showing clinical, radiological and functional benefits. The literature available points to a decrease in mortality, but we could not affirm so in our small population.

[Vitamin B12 Deficiency in Type 2 Diabetes Mellitus].

PubMed

Tavares Bello, Carlos; Capitão, Ricardo Miguel; Sequeira Duarte, João; Azinheira, Jorge; Vasconcelos, Carlos

2017-10-31

Type 2 diabetes mellitus is a common disease, affecting up to 13.1% of the Portuguese population. In addition to the known micro and macrovascular complications, drug side effects constitute a major concern, leading to changes in the treatment guidelines, which favor safety over efficacy. Metformin is the first-line pharmacological treatment for most patients with type 2 diabetes mellitus; however, it has been associated with vitamin B12 deficiency in up to 30% of treated patients. The authors describe the prevalence of vitamin B12 deficiency in a diabetic population and explore the possible underlying factors. Retrospective, observational study. Clinical and laboratory data of type 2 diabetes mellitus patients whose vitamin B12 status was evaluated in the last decade (2005 - 2016) were analyzed. Patients with known malabsorptive syndromes or having undergone bariatric surgery were excluded from the study. Statistical analysis of the data was done and the results were considered statistically significant at p values < 0.05. The study included a total of 1007 patients (58% women) with a mean age of 66.4 ± 12.2 years and 11 ± 10.4 years of type 2 diabetes mellitus duration. These patients had a high prevalence of complications: diabetic renal disease 47.7%, neuropathy 9.2%, retinopathy 14.9%, coronary artery disease 8.4%, cerebrovascular disease 10.9%, and peripheral arterial disease 5.5%. Vitamin B12 deficiency (< 174 ng / dL) was present in 21.4% of the population and this subgroup was older (68.4 vs 65.8 years, p = 0.006), had a longer type 2 diabetes mellitus duration (13.35 vs 10.36 years; p = 0.001), higher prevalence of retinopathy (20.9% vs 13.3%; p = 0.005) and thyroid dysfunction (34% vs 23.7%; p = 0.002). Vitamin B12 deficiency was also more frequent in patients treated with metformin (24.7% vs 15.8%; p = 0.017), antiplatelet agents (25.4% vs 16.2%, p < 0.001), and calcium channel blockers (26.8% vs 18.2%; p = 0.001). After adjustment for possible

Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia.

PubMed

Le Sommer, Samantha; Morrice, Nicola; Pesaresi, Martina; Thompson, Dawn; Vickers, Mark A; Murray, Graeme I; Mody, Nimesh; Neel, Benjamin G; Bence, Kendra K; Wilson, Heather M; Delibegović, Mirela

2018-01-01

Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B -/- mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75-87. ©2017 AACR . ©2017 American Association for Cancer Research.

Developmental vitamin D deficiency and schizophrenia: the role of animal models.

PubMed

Schoenrock, S A; Tarantino, L M

2016-01-01

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Improved Starch Digestion of Sucrase-deficient Shrews Treated With Oral Glucoamylase Enzyme Supplements.

PubMed

Nichols, Buford L; Avery, Stephen E; Quezada-Calvillo, Roberto; Kilani, Shadi B; Lin, Amy Hui-Mei; Burrin, Douglas G; Hodges, Benjamin E; Chacko, Shaji K; Opekun, Antone R; Hindawy, Marwa El; Hamaker, Bruce R; Oda, Sen-Ichi

2017-08-01

Although named because of its sucrose hydrolytic activity, this mucosal enzyme plays a leading role in starch digestion because of its maltase and glucoamylase activities. Sucrase-deficient mutant shrews, Suncus murinus, were used as a model to investigate starch digestion in patients with congenital sucrase-isomaltase deficiency.Starch digestion is much more complex than sucrose digestion. Six enzyme activities, 2 α-amylases (Amy), and 4 mucosal α-glucosidases (maltases), including maltase-glucoamylase (Mgam) and sucrase-isomaltase (Si) subunit activities, are needed to digest starch to absorbable free glucose. Amy breaks down insoluble starch to soluble dextrins; mucosal Mgam and Si can either directly digest starch to glucose or convert the post-α-amylolytic dextrins to glucose. Starch digestion is reduced because of sucrase deficiency and oral glucoamylase enzyme supplement can correct the starch maldigestion. The aim of the present study was to measure glucogenesis in suc/suc shrews after feeding of starch and improvement of glucogenesis by oral glucoamylase supplements. Sucrase mutant (suc/suc) and heterozygous (+/suc) shrews were fed with C-enriched starch diets. Glucogenesis derived from starch was measured as blood C-glucose enrichment and oral recombinant C-terminal Mgam glucoamylase (M20) was supplemented to improve starch digestion. After feedings, suc/suc and +/suc shrews had different starch digestions as shown by blood glucose enrichment and the suc/suc had lower total glucose concentrations. Oral supplements of glucoamylase increased suc/suc total blood glucose and quantitative starch digestion to glucose. Sucrase deficiency, in this model of congenital sucrase-isomaltase deficiency, reduces blood glucose response to starch feeding. Supplementing the diet with oral recombinant glucoamylase significantly improved starch digestion in the sucrase-deficient shrew.

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

CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

PubMed Central

Xu, Hong; Di Antonio, Marco; McKinney, Steven; Mathew, Veena; Ho, Brandon; O'Neil, Nigel J.; Santos, Nancy Dos; Silvester, Jennifer; Wei, Vivien; Garcia, Jessica; Kabeer, Farhia; Lai, Daniel; Soriano, Priscilla; Banáth, Judit; Chiu, Derek S.; Yap, Damian; Le, Daniel D.; Ye, Frank B.; Zhang, Anni; Thu, Kelsie; Soong, John; Lin, Shu-chuan; Tsai, Angela Hsin Chin; Osako, Tomo; Algara, Teresa; Saunders, Darren N.; Wong, Jason; Xian, Jian; Bally, Marcel B.; Brenton, James D.; Brown, Grant W.; Shah, Sohrab P.; Cescon, David; Mak, Tak W.; Caldas, Carlos; Stirling, Peter C.; Hieter, Phil; Balasubramanian, Shankar; Aparicio, Samuel

2017-01-01

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016). PMID:28211448

CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours.

PubMed

Xu, Hong; Di Antonio, Marco; McKinney, Steven; Mathew, Veena; Ho, Brandon; O'Neil, Nigel J; Santos, Nancy Dos; Silvester, Jennifer; Wei, Vivien; Garcia, Jessica; Kabeer, Farhia; Lai, Daniel; Soriano, Priscilla; Banáth, Judit; Chiu, Derek S; Yap, Damian; Le, Daniel D; Ye, Frank B; Zhang, Anni; Thu, Kelsie; Soong, John; Lin, Shu-Chuan; Tsai, Angela Hsin Chin; Osako, Tomo; Algara, Teresa; Saunders, Darren N; Wong, Jason; Xian, Jian; Bally, Marcel B; Brenton, James D; Brown, Grant W; Shah, Sohrab P; Cescon, David; Mak, Tak W; Caldas, Carlos; Stirling, Peter C; Hieter, Phil; Balasubramanian, Shankar; Aparicio, Samuel

2017-02-17

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).

[Prevalence of iron deficiency].

PubMed

Dupont, C

2017-05-01

Studies of prévalence in iron deficiency separate iron depletion (defined as decreased blood ferritin) and iron deficiency anemia (defined as blood decrease in both ferritin and hemoglobin). In Europe, most studies are outdated. Prevalence of iron depletion varies from 7 to 18 % and 24 to 36% in toddlers and adolescents, respectively. Prevalence of iron deficiency anemia varies from 2 to 8.5% and 7 to 10% in toddlers and adolescents. In French speaking African countries, Demography Health Surveys show that 80% of children aged 0 to 2 years are anemic, severely for 5 to 9% of them. © 2017 Elsevier Masson SAS. Tous droits réservés.

Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

PubMed Central

Hopkinson, Mark; Poulet, Blandine; Pollard, Andrea S.; Shefelbine, Sandra J.; Chang, Yu-Mei; Francis-West, Philippa; Bou-Gharios, George; Pitsillides, Andrew A.

2016-01-01

Tissue inhibitor of metalloproteinases-3 (TIMP-3) regulates extracellular matrix via its inhibition of matrix metalloproteinases and membrane-bound sheddases. Timp-3 is expressed at multiple sites of extensive tissue remodelling. This extends to bone where its role, however, remains largely unresolved. In this study, we have used Micro-CT to assess bone mass and architecture, histological and histochemical evaluation to characterise the skeletal phenotype of Timp-3 KO mice and have complemented this by also examining similar indices in mice harbouring a Timp-3 transgene driven via a Col-2a-driven promoter to specifically target overexpression to chondrocytes. Our data show that Timp-3 deficiency compromises tibial bone mass and structure in both cortical and trabecular compartments, with corresponding increases in osteoclasts. Transgenic overexpression also generates defects in tibial structure predominantly in the cortical bone along the entire shaft without significant increases in osteoclasts. These alterations in cortical mass significantly compromise predicted tibial load-bearing resistance to torsion in both genotypes. Neither Timp-3 KO nor transgenic mouse growth plates are significantly affected. The impact of Timp-3 deficiency and of transgenic overexpression extends to produce modification in craniofacial bones of both endochondral and intramembranous origins. These data indicate that the levels of Timp-3 are crucial in the attainment of functionally-appropriate bone mass and architecture and that this arises from chondrogenic and osteogenic lineages. PMID:27519049

Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure

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

Yasuda-Yamahara, Mako; Kume, Shinji, E-mail: skume@belle.shiga-med.ac.jp; Yamahara, Kosuke

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with highermore » energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. - Highlights: • Lamp-2 is essential for autophagosome fusion with lysosome and its degradation. • Lamp-2 deficiency lead to a resistance to diet-induced obese diabetes in mice. • Lamp-2 deficiency increased whole body energy expenditure under HFD-feeding. • Lamp-2 deficiency elevated the serum level of FGF21 under HFD-feeding.« less

Vitamin D Deficiency in Patients with Acute Myocardial Infarction: An Italian Single-Center Study.

PubMed

Aleksova, Aneta; Belfiore, Rita; Carriere, Cosimo; Kassem, Salam; La Carrubba, Salvatore; Barbati, Giulia; Sinagra, Gianfranco

2015-01-01

Hypovitaminosis D is a vitamin deficiency that has been increasing in developed countries; it was also suggested as an emerging risk factor for developing of atherosclerosis and acute myocardial infarction. The primary source of vitamin D is its cutaneous synthesis under exposure to sunlight. It has been suggested that 30 min of sun exposure twice weekly leads to sufficient vitamin D synthesis. The residents of Trieste (Italy) are well-known for their high exposure to sunlight in all seasons. We aimed to investigate the vitamin D status in subjects with acute myocardial infarction living in this area. Vitamin D status was identified in 478 subjects diagnosed with acute myocardial infarction. The median serum 25-hydroxyvitamin D concentration was 14.5 [7.8 - 22.7] ng/mL. Vitamin D deficiency and insufficiency were present in 324 (68 %) and 107 (22 %) subjects, respectively. Vitamin D deficiency was less frequent among subjects enrolled in the period from July to the end of September (p < 0.001). In a multivariate analysis vitamin D deficiency was predicted by older age (p = 0.02), female gender (p = 0.002), higher body mass index (p = 0.05), autumn/winter sampling (p < 0.001), increased parathyroid hormone (p = 0.03) and alkaline phosphatase (p = 0.003). We observed very high prevalence of vitamin D deficiency among subjects with myocardial infarction in all seasons of enrollment. However, it was lower in the summer when sun exposure is higher. The exposure to sunlight may be a cost-saving therapeutic strategy for the management of vitamin D deficiency.

Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review.

PubMed

Daru, J; Allotey, J; Peña-Rosas, J P; Khan, K S

2017-06-01

The aim of this review was to understand the landscape of serum ferritin in diagnosing iron deficiency in the aetiology of anaemia in pregnancy. Iron deficiency in pregnancy is a major public health problem leading to the development of anaemia. Reducing the global prevalence of anaemia in women of reproductive age is a 2025 global nutrition target. Bone marrow aspiration is the gold standard test for iron deficiency but requires an invasive procedure; therefore, serum ferritin is the most clinically useful test. We undertook a systematic search of electronic databases and trial registers from inception to January 2016. Studies of iron or micronutrient supplementation in pregnancy with pre-defined serum ferritin thresholds were included. Two independent reviewers selected studies, extracted data and assessed quality. There were 76 relevant studies mainly of observational study design (57%). The most commonly used thresholds of serum ferritin for the diagnosis of iron deficiency were <12 and <15 ng mL -1 (68%). Most primary studies provided no justification for the choice of serum ferritin threshold used, but 25 studies (33%) used thresholds defined by expert consensus in a guideline development process. There were five studies (7%) using a serum ferritin threshold defining iron deficiency derived from primary studies of bone marrow aspiration. Unified international thresholds of iron deficiency for women throughout pregnancy are required for accurate assessments of the global disease burden and for evaluating effectiveness of interventions addressing this problem. © 2017 World Health Organization licensed by Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.

Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.

PubMed

Sandau, Ursula S; Colino-Oliveira, Mariana; Jones, Abbie; Saleumvong, Bounmy; Coffman, Shayla Q; Liu, Long; Miranda-Lourenço, Catarina; Palminha, Cátia; Batalha, Vânia L; Xu, Yiming; Huo, Yuqing; Diógenes, Maria J; Sebastião, Ana M; Boison, Detlev

2016-11-30

Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adk fl/fl mice. These Adk Δbrain mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A 1 receptor (A 1 R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A 2A receptor (A 2A R) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A 2A receptor activity in Adk Δbrain mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A 2A R activity therapeutically can attenuate neurological symptoms in ADK deficiency. A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy

Malonyl CoA decarboxylase deficiency: C to T transition in intron 2 of the MCD gene.

PubMed

Surendran, S; Sacksteder, K A; Gould, S J; Coldwell, J G; Rady, P L; Tyring, S K; Matalon, R

2001-09-15

Malonyl CoA decarboxylase (MCD) is an enzyme involved in the metabolism of fatty acids synthesis. Based on reports of MCD deficiency, this enzyme is particular important in muscle and brain metabolism. Mutations in the MCD gene result in a deficiency of MCD activity, that lead to psychomotor retardation, cardiomyopathy and neonatal death. To date however, only a few patients have been reported with defects in MCD. We report here studies of a patient with MCD deficiency, who presented with hypotonia, cardiomyopathy and psychomotor retardation. DNA sequencing of MCD revealed a homozygous intronic mutation, specifically a -5 C to T transition near the acceptor site for exon 3. RT-PCR amplification of exons 2 and 3 revealed that although mRNA from a normal control sample yielded one major DNA band, the mutant mRNA sample resulted in two distinct DNA fragments. Sequencing of the patient's two RT-PCR products revealed that the larger molecular weight fragments contained exons 2 and 3 as well as the intervening intronic sequence. The smaller size band from the patient contained the properly spliced exons, similar to the normal control. Western blotting analysis of the expressed protein showed only a faint band in the patient sample in contrast to a robust band in the control. In addition, the enzyme activity of the mutant protein was lower than that of the control protein. The data indicate that homozygous mutation in intron 2 disrupt normal splicing of the gene, leading to lower expression of the MCD protein and MCD deficiency. Copyright 2001 Wiley-Liss, Inc.

Iron-deficient erythropoiesis in blood donors and red blood cell recovery after transfusion: initial studies with a mouse model

PubMed Central

Bandyopadhyay, Sheila; Brittenham, Gary M.; Francis, Richard O.; Zimring, James C.; Hod, Eldad A.; Spitalnik, Steven L.

2017-01-01

Background Most frequent red cell (RBC) donors and many first-time donors are iron deficient, but meet haemoglobin standards. However, the effects of donation-induced iron deficiency on RBC storage quality are unknown. Thus, we used a mouse model to determine if donor iron deficiency reduced post-transfusion RBC recovery. Methods Weanling mice received a control diet or an iron-deficient diet. A third group receiving the iron-deficient diet was also phlebotomised weekly. This provided 3 groups of mice with different iron status: (1) iron replete, (2) mild iron deficiency with iron-deficient erythropoiesis, and (3) iron-deficiency anaemia. At ten weeks of age, blood was collected, leucoreduced, and stored at 4 ºC. After 12 days of storage, 24-hour (h) post-transfusion RBC recovery was quantified in recipients by flow cytometry. Results Before blood collection, mean haemoglobin concentrations in the iron-replete, iron-deficient, and iron-deficiency anaemia donor mice were 16.5±0.4, 11.5±0.4, and 7.0±1.4 [g/dL± 1 standard deviation (SD)], respectively (p<0.01 for all comparisons between groups). The 24-h post-transfusion RBC recoveries in recipients receiving transfusions from these three cohorts were 77.1±13.2, 66.5±10.9, and 46.7±15.9 (% ±1 SD), respectively (p<0.05 for all comparisons between groups). Discussion In summary, donor iron deficiency significantly reduced 24-h post-transfusion RBC recovery in recipient mice. RBCs from mice with mild iron deficiency and iron-deficient erythropoiesis, with haemoglobin levels similar to those used for human autologous blood donation, had intermediate post-transfusion RBC recovery, as compared to iron-replete donors and those with iron-deficiency anaemia. This suggests that, in addition to the effects of iron deficiency on donor health, frequent blood donation, leading to iron-deficient erythropoiesis, may also have adverse effects for transfusion recipients. PMID:28263174

Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets

PubMed Central

Glorieux, Francis H; Pettifor, John M

2014-01-01

This review describes the pathogenesis, clinical presentation and biochemical perturbations found in privational (nutritional) rickets and pseudo-vitamin D deficiency rickets (PDDR), an autosomal recessive condition with loss of function mutations in CYP27B1. It may seem strange to combine a discussion on privational rickets and PDDR as a single topic, but privational rickets and PDDR present with similar clinical signs and symptoms and with similar perturbations in bone and mineral metabolism. Of interest is the characteristic lack of features of rickets at birth in infants with PDDR, a finding which has also been reported in infants born to vitamin D-deficient mothers. This highlights the independence of the fetus and neonate from the need for vitamin D to maintain calcium homeostasis during this period. The variable roles of vitamin D deficiency and dietary calcium deficiency in the pathogenesis of privational rickets are discussed and the associated alterations in vitamin D metabolism highlighted. Although PDDR is a rare autosomal recessive disorder, results of long-term follow-up are now available on the effect of treatment with calcitriol, and these are discussed. Areas of uncertainty, such as should affected mothers breastfeed their infants, are emphasized. PMID:24818008

Heart Failure and the Iron Deficiency.

PubMed

Beedkar, Amey; Parikh, Rohan; Deshmukh, Pradeep

2017-11-01

Iron deficiency anemia is a significant problem worldwide and more so in developing countries, like India. The prevention and treatment of iron deficiency is a major public health goal in India It is now well recognized that iron deficiency has detrimental effects in patients with coronary artery disease, heart failure, and pulmonary hypertension, and possibly in patients undergoing cardiac surgery. Around one-third of all patients with HF, and around one-half of patients with pulmonary hypertension, are affected by iron deficiency.1. © Journal of the Association of Physicians of India 2011.

Isolated sulfite oxidase deficiency.

PubMed

Rupar, C A; Gillett, J; Gordon, B A; Ramsay, D A; Johnson, J L; Garrett, R M; Rajagopalan, K V; Jung, J H; Bacheyie, G S; Sellers, A R

1996-12-01

Isolated sulfite oxidase (SO) deficiency is an autosomal recessively inherited inborn error of sulfur metabolism. In this report of a ninth patient the clinical history, laboratory results, neuropathological findings and a mutation in the sulfite oxidase gene are described. The data from this patient and previously published patients with isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are summarized to characterize this rare disorder. The patient presented neonatally with intractable seizures and did not progress developmentally beyond the neonatal stage. Dislocated lenses were apparent at 2 months. There was increased urine excretion of sulfite and S-sulfocysteine and a decreased concentration of plasma cystine. A lactic acidemia was present for 6 months. Liver sulfite oxidase activity was not detectable but xanthine dehydrogenase activity was normal. The boy died of respiratory failure at 32 months. Neuropathological findings of cortical necrosis and extensive cavitating leukoencephalopathy were reminiscent of those seen in severe perinatal asphyxia suggesting an etiology of energy deficiency. A point mutation that resulted in a truncated protein missing the molybdenum-binding site has been identified.

Dietary imbalances in a large breed puppy, leading to compression fractures, vitamin D deficiency, and suspected nutritional secondary hyperparathyroidism.

PubMed

Tal, Moran; Parr, Jacqueline M; MacKenzie, Shawn; Verbrugghe, Adronie

2018-01-01

A 6-month-old intact female giant schnauzer dog fed a nutritionally unbalanced homemade diet was evaluated because of a 1-month history of lameness and difficulty walking. Abnormalities identified on ancillary tests, in conjunction with the dog's clinical improvement following diet change, suggested a diagnosis of vitamin D deficiency and nutritional secondary hyperparathyroidism. This report underlines the importance of appropriate feeding management, especially during the vulnerable growth phase.

Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats.

PubMed

Abe, Ikumi; Shirato, Ken; Hashizume, Yoko; Mitsuhashi, Ryosuke; Kobayashi, Ayumu; Shiono, Chikako; Sato, Shogo; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

2013-01-01

Folate (vitamin B(9)) plays key roles in cell growth and proliferation through regulating the synthesis and stabilization of DNA and RNA, and its deficiency leads to lymphocytopenia and granulocytopenia. However, precisely how folate deficiency affects the distribution of a variety of white blood cell subsets, including the minor population of basophils, and the cell specificity of the effects remain unclear. Therefore, we examined the effects of a folate-deficient diet on the circulating number of lymphocyte subsets [T-lymphocytes, B-lymphocytes, and natural killer (NK) cells] and granulocyte subsets (neutrophils, eosinophils, and basophils) in rats. Rats were divided into two groups, with one receiving the folate-deficient diet (FAD group) and the other a control diet (CON group). All rats were pair-fed for 8 weeks. Plasma folate level was dramatically lower in the FAD group than in the CON group, and the level of homocysteine in the plasma, a predictor of folate deficiency was significantly higher in the FAD group than in the CON group. The number of T-lymphocytes, B-lymphocytes, and NK cells was significantly lower in the FAD group than in the CON group by 0.73-, 0.49-, and 0.70-fold, respectively, indicating that B-lymphocytes are more sensitive to folate deficiency than the other lymphocyte subsets. As expected, the number of neutrophils and eosinophils was significantly lower in the FAD group than in the CON group. However, the number of basophils, the least common type of granulocyte, showed transiently an increasing tendency in the FAD group as compared with the CON group. These results suggest that folate deficiency induces lymphocytopenia and granulocytopenia in a cell-specific manner.

Genetics Home Reference: fumarase deficiency

MedlinePlus

... C, Knape M, Zierz S, Gellerich FN. Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab. 2006 ... Y, Toulhoat H, de Lonlay P. Clinical and biochemical heterogeneity associated with fumarase deficiency. Hum Mutat. 2011 ...

Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells.

PubMed

Saffi, Jenifer; Agnoletto, Mateus H; Guecheva, Temenouga N; Batista, Luís F Z; Carvalho, Helotonio; Henriques, João A P; Stary, Anne; Menck, Carlos F M; Sarasin, Alain

2010-01-02

Doxorubicin (DOX), a member of the anthracycline group, is a widely used drug in cancer therapy. The mechanisms of DOX action include topoisomerase II-poisoning, free radical release, DNA adducts and interstrand cross-link (ICL) formation. Nucleotide excision repair (NER) is involved in the removal of helix-distorting lesions and chemical adducts, however, little is known about the response of NER-deficient cell lines to anti-tumoral drugs like DOX. Wild type and XPD-mutated cells, harbouring mutations in different regions of this gene and leading to XP-D, XP/CS or TTD diseases, were treated with this drug and analyzed for cell cycle arrest and DNA damage by comet assay. The formation of DSBs was also investigated by determination of gammaH2AX foci. Our results indicate that all three NER-deficient cell lines tested are more sensitive to DOX treatment, when compared to wild type cells or XP cells complemented by the wild type XPD cDNA, suggesting that NER is involved in the removal of DOX-induced lesions. The cell cycle analysis showed the characteristic G2 arrest in repair-proficient MRC5 cell line after DOX treatment, whereas the repair-deficient cell lines presented significant increase in sub-G1 fraction. The NER-deficient cell lines do not show different patterns of DNA damage formation as assayed by comet assay and phosphorylated H2AX foci formation. Knock-down of topoisomerase IIalpha with siRNA leads to increased survival in both MRC5 and XP cells, however, XP cell line still remained significantly more sensitive to the treatment by DOX. Our study suggests that the enhanced sensitivity is due to DOX-induced DNA damage that is subject to NER, as we observed decreased unscheduled DNA synthesis in XP-deficient cells upon DOX treatment. Furthermore, the complementation of the XPD-function abolished the observed sensitivity at lower DOX concentrations, suggesting that the XPD helicase activity is involved in the repair of DOX-induced lesions. Copyright (c) 2009

Parkin Deficiency Reduces Hippocampal Glutamatergic Neurotransmission by Impairing AMPA Receptor Endocytosis.

PubMed

Cortese, Giuseppe P; Zhu, Mei; Williams, Damian; Heath, Sarah; Waites, Clarissa L

2016-11-30

Mutations in the gene encoding Parkin, an E3 ubiquitin ligase, lead to juvenile-onset Parkinson's disease by inducing the selective death of midbrain dopaminergic neurons. Accumulating evidence indicates that Parkin also has an important role in excitatory glutamatergic neurotransmission, although its precise mechanism of action remains unclear. Here, we investigate Parkin's role at glutamatergic synapses of rat hippocampal neurons. We find that Parkin-deficient neurons exhibit significantly reduced AMPA receptor (AMPAR)-mediated currents and cell-surface expression, and that these phenotypes result from decreased postsynaptic expression of the adaptor protein Homer1, which is necessary for coupling AMPAR endocytic zones with the postsynaptic density. Accordingly, Parkin loss of function leads to the reduced density of postsynaptic endocytic zones and to impaired AMPAR internalization. These findings demonstrate a novel and essential role for Parkin in glutamatergic neurotransmission, as a stabilizer of postsynaptic Homer1 and the Homer1-linked endocytic machinery necessary for maintaining normal cell-surface AMPAR levels. Mutations in Parkin, a ubiquitinating enzyme, lead to the selective loss of midbrain dopaminergic neurons and juvenile-onset Parkinson's disease (PD). Parkin loss of function has also been shown to alter hippocampal glutamatergic neurotransmission, providing a potential explanation for PD-associated cognitive impairment. However, very little is known about Parkin's specific sites or mechanisms of action at glutamatergic synapses. Here, we show that Parkin deficiency leads to decreased AMPA receptor-mediated activity due to disruption of the postsynaptic endocytic zones required for maintaining proper cell-surface AMPA receptor levels. These findings demonstrate a novel role for Parkin in synaptic AMPA receptor internalization and suggest a Parkin-dependent mechanism for hippocampal dysfunction that may explain cognitive deficits associated with

DUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis

PubMed Central

Musumeci, Lucia; Kuijpers, Marijke J; Gilio, Karen; Hego, Alexandre; Théâtre, Emilie; Maurissen, Lisbeth; Vandereyken, Maud; Diogo, Catia V; Lecut, Christelle; Guilmain, William; Bobkova, Ekaterina V; Eble, Johannes A.; Dahl, Russell; Drion, Pierre; Rascon, Justin; Mostofi, Yalda; Yuan, Hongbin; Sergienko, Eduard; Chung, Thomas DY; Thiry, Marc; Senis, Yotis; Moutschen, Michel; Mustelin, Tomas; Lancellotti, Patrizio; Heemskerk, Johan WM; Tautz, Lutz; Oury, Cécile; Rahmouni, Souad

2015-01-01

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. PMID:25520375

Clinical features of patients with homozygous complement C4A or C4B deficiency.

PubMed

Liesmaa, Inka; Paakkanen, Riitta; Järvinen, Asko; Valtonen, Ville; Lokki, Marja-Liisa

2018-01-01

Homozygous deficiencies of complement C4A or C4B are detected in 1-10% of populations. In genome-wide association studies C4 deficiencies are missed because the genetic variation of C4 is complex. There are no studies where the clinical presentation of these patients is analyzed. This study was aimed to characterize the clinical features of patients with homozygous C4A or C4B deficiency. Thirty-two patients with no functional C4A, 87 patients with no C4B and 120 with normal amount of C4 genes were included. C4A and C4B numbers were assessed with genomic quantitative real-time PCR. Medical history was studied retrospectively from patients' files. Novel associations between homozygous C4A deficiency and lymphoma, coeliac disease and sarcoidosis were detected. These conditions were present in 12.5%, (4/32 in patients vs. 0.8%, 1/120, in controls, OR = 17.00, 95%CI = 1.83-158.04, p = 0.007), 12.5% (4/32 in patients vs. 0%, 0/120 in controls, OR = 1.14, 95%CI = 1.00-1.30, p = 0.002) and 12.5%, respectively (4/32 in patients vs. 2.5%, 3/120 in controls, OR = 5.571, 95%CI = 1.79-2.32, p = 0.036). In addition, C4A and C4B deficiencies were both associated with adverse drug reactions leading to drug discontinuation (34.4%, 11/32 in C4A-deficient patients vs. 14.2%, 17/120 in controls, OR = 3.174, 95%CI = 1.30-7.74, p = 0.009 and 28.7%, 25/87 in C4B-deficient patients, OR = 2.44, 95%CI = 1.22-4.88, p = 0.010). This reported cohort of homozygous deficiencies of C4A or C4B suggests that C4 deficiencies may have various unrecorded disease associations. C4 gene should be considered as a candidate gene in studying these selected disease associations.

Microbial ecology perturbation in human IgA deficiency.

PubMed

Fadlallah, Jehane; El Kafsi, Hela; Sterlin, Delphine; Juste, Catherine; Parizot, Christophe; Dorgham, Karim; Autaa, Gaëlle; Gouas, Doriane; Almeida, Mathieu; Lepage, Patricia; Pons, Nicolas; Le Chatelier, Emmanuelle; Levenez, Florence; Kennedy, Sean; Galleron, Nathalie; de Barros, Jean-Paul Pais; Malphettes, Marion; Galicier, Lionel; Boutboul, David; Mathian, Alexis; Miyara, Makoto; Oksenhendler, Eric; Amoura, Zahir; Doré, Joel; Fieschi, Claire; Ehrlich, S Dusko; Larsen, Martin; Gorochov, Guy

2018-05-02

Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the forefront of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Reward deficiency and anti-reward in pain chronification.

PubMed

Borsook, D; Linnman, C; Faria, V; Strassman, A M; Becerra, L; Elman, I

2016-09-01

Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification). Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Thiamine deficiency in Cambodian infants with and without beriberi.

PubMed

Coats, Debra; Shelton-Dodge, Kelsey; Ou, Kevanna; Khun, Vannara; Seab, Sommon; Sok, Kimsan; Prou, Chiva; Tortorelli, Silvia; Moyer, Thomas P; Cooper, Lisa E; Begley, Tadhg P; Enders, Felicity; Fischer, Philip R; Topazian, Mark

2012-11-01

To test the hypothesis that heavy metal toxicity and consumption of thiaminase-containing foods predispose to symptomatic thiamine deficiency. In a case-control study, thiamine diphosphate (TDP) blood concentrations were measured in 27 infants diagnosed with beriberi at a rural clinic, as well as their mothers and healthy Cambodian and American controls. Blood and urine levels of lead, arsenic, cadmium, mercury, and thallium were measured. Local food samples were analyzed for thiaminase activity. Mean TDP level among cases and Cambodian controls was 48 and 56 nmol/L, respectively (P = .08) and was 132 nmol/L in American controls (P < .0001 compared with both Cambodian groups). Mean TDP level of mothers of cases and Cambodian controls was 57 and 57 nmol/L (P = .92), and was 126 nmol/L in American mothers (P < .0001 compared with both Cambodian groups). Cases (but not controls) had lower blood TDP levels than their mothers (P = .02). Infant TDP level decreased with infant age and was positively associated with maternal TDP level. Specific diagnostic criteria for beriberi did not correlate with TDP level. There was no correlation between heavy metal levels and either TDP level or case/control status. No thiaminase activity was observed in food samples. Thiamine deficiency is endemic among infants and nursing mothers in rural southeastern Cambodia and is often clinically inapparent. Neither heavy metal toxicity nor consumption of thiaminase-containing foods account for thiamine deficiency in this region. Copyright © 2012 Mosby, Inc. All rights reserved.

Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring via Panx1 hypermethylation.

PubMed

Meems, Laura M G; Mahmud, Hasan; Buikema, Hendrik; Tost, Jörg; Michel, Sven; Takens, Janny; Verkaik-Schakel, Rikst N; Vreeswijk-Baudoin, Inge; Mateo-Leach, Irene V; van der Harst, Pim; Plösch, Torsten; de Boer, Rudolf A

2016-12-01

Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring. Copyright © 2016 the American Physiological Society.

MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells.

PubMed

Campregher, Christoph; Schmid, Gerald; Ferk, Franziska; Knasmüller, Siegfried; Khare, Vineeta; Kortüm, Benedikt; Dammann, Kyle; Lang, Michaela; Scharl, Theresa; Spittler, Andreas; Roig, Andres I; Shay, Jerry W; Gerner, Christopher; Gasche, Christoph

2012-01-01

Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency. HCT116 and HCT116+chr3 (both MSH3-deficient) and primary human colon epithelial cells (HCEC, MSH3-wildtype) were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs) were assessed by Comet assay. Despite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10(-4)) at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50), apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold. MSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon carcinogenesis.

Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.

PubMed

Katayama, K; Yamada, K; Ornthanalai, V G; Inoue, T; Ota, M; Murphy, N P; Aruga, J

2010-02-01

Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an alpha2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plus-maze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency.

PubMed

García-Corzo, Laura; Luna-Sánchez, Marta; Doerrier, Carolina; García, José A; Guarás, Adela; Acín-Pérez, Rebeca; Bullejos-Peregrín, Javier; López, Ana; Escames, Germaine; Enríquez, José A; Acuña-Castroviejo, Darío; López, Luis C

2013-03-15

Coenzyme Q10 (CoQ(10)) or ubiquinone is a well-known component of the mitochondrial respiratory chain. In humans, CoQ(10) deficiency causes a mitochondrial syndrome with an unexplained variability in the clinical presentations. To try to understand this heterogeneity in the clinical phenotypes, we have generated a Coq9 Knockin (R239X) mouse model. The lack of a functional Coq9 protein in homozygous Coq9 mutant (Coq9(X/X)) mice causes a severe reduction in the Coq7 protein and, as consequence, a widespread CoQ deficiency and accumulation of demethoxyubiquinone. The deficit in CoQ induces a brain-specific impairment of mitochondrial bioenergetics performance, a reduction in respiratory control ratio, ATP levels and ATP/ADP ratio and specific loss of respiratory complex I. These effects lead to neuronal death and demyelinization with severe vacuolization and astrogliosis in the brain of Coq9(X/X) mice that consequently die between 3 and 6 months of age. These results suggest that the instability of mitochondrial complex I in the brain, as a primary event, triggers the development of mitochondrial encephalomyopathy associated with CoQ deficiency.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood.

PubMed

Wong-Goodrich, Sarah J E; Tognoni, Christina M; Mellott, Tiffany J; Glenn, Melissa J; Blusztajn, Jan K; Williams, Christina L

2011-09-21

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. Copyright © 2011 Elsevier B.V. All rights reserved.

Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice.

PubMed

Bélanger, Simon; Tu, Megan M; Rahim, Mir Munir Ahmed; Mahmoud, Ahmad B; Patel, Rajen; Tai, Lee-Hwa; Troke, Angela D; Wilhelm, Brian T; Landry, Josette-Renée; Zhu, Qinzhang; Tung, Kenneth S; Raulet, David H; Makrigiannis, Andrew P

2012-07-19

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.

Iron deficiency--facts and fallacies.

PubMed

Oski, F A

1985-04-01

Iron deficiency occurs in all strata of society, is primarily a result of postnatal feeding practices and not due to congenital deficiencies of iron, can be prevented by appropriate dietary guidance, and, when present, produces important nonhematologic manifestations.

Diagnosis of thalassemia and iron deficiency anemia using confocal and atomic force microscopy

NASA Astrophysics Data System (ADS)

Tariq, Saira; Bilal, Muhammad; Shahzad, Shaheen; Firdous, Shamaraz; Aziz, Uzma; Ahmed, Mushtaq

2017-11-01

Anemia is the most prevalent blood disorder, categorized into thalassemia and iron deficiency anemia. In anemia, the morphology of erythrocytes is disturbed, thus leading to abnormal functioning of the erythrocytes. Globally, thalassemia affects 1.3% of individuals and is one of the most widespread monogenic disorders in Pakistan. All over the World, women and children are most frequently affected by a type of nutritional deficiency known as iron deficiency anemia. The morphological changes that occur in erythrocytes due to these diseases are investigated in this study at the nano-scale level. Fifty samples of blood from individuals suffering from thalassemia or iron deficiency anemia were obtained from different hospitals in Rawalpindi and Islamabad. The blood samples were scanned using atomic force microscopy (AFM) and laser scanning confocal microscopy (LSCM) to check the morphological changes in both types of anemia. According to the present study, thalassemia is most prevalent in females in the age group between 5 and 15 years old, and iron deficiency is most prevalent in females in the age groups of 16-25 and 36-45 years old. Erythrocyte morphology is the significant determinant for diagnosing and discriminating between these two types of diseases. The study reports deformed erythrocytes in anemic patients, which were different from the ones that existed in the control. Thalassemia erythrocytes showed a crenated shape, iron deficiency anemia erythrocytes showed an elliptocyte shape and healthy erythrocytes showed a biconcave disk shape when using AFM and LSCM. These techniques seem to be very promising, cheap and less time consuming in determining the structure-function relationship of erythrocytes of thalassemic and iron deficiency anemic patients. The results of LSCM and AFM are quite useful in determining the morphological changes in erythrocytes and to study the disease at the molecular level within short period of time. Hence, we encourage employing

Renal sodium transport in renin-deficient Dahl salt-sensitive rats

PubMed Central

Pavlov, Tengis S; Levchenko, Vladislav; Ilatovskaya, Daria V; Moreno, Carol; Staruschenko, Alexander

2016-01-01

Objective: The Dahl salt-sensitive rat is a well-established model of salt-sensitive hypertension. The goal of this study was to assess the expression and activity of renal sodium channels and transporters in the renin-deficient salt-sensitive rat. Methods: Renin knockout (Ren−/−) rats created on the salt-sensitive rat background were used to investigate the role of renin in the regulation of ion transport in salt-sensitive hypertension. Western blotting and patch-clamp analyses were utilized to assess the expression level and activity of Na+ transporters. Results: It has been described previously that Ren−/− rats exhibit severe kidney underdevelopment, polyuria, and lower body weight and blood pressure compared to their wild-type littermates. Here we found that renin deficiency led to decreased expression of sodium-hydrogen antiporter (NHE3), the Na+/H+ exchanger involved in Na+ absorption in the proximal tubules, but did not affect the expression of Na-K-Cl cotransporter (NKCC2), the main transporter in the loop of Henle. In the distal nephron, the expression of sodium chloride cotransporter (NCC) was lower in Ren−/− rats. Single-channel patch clamp analysis detected decreased ENaC activity in Ren−/− rats which was mediated via changes in the channel open probability. Conclusion: These data illustrate that renin deficiency leads to significant dysregulation of ion transporters. PMID:27443990

[Causes of iron deficiency in children].

PubMed

Olives, J-P

2017-05-01

Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children. In developing countries, iron deficiency is caused by poor iron intake and parasitic infection. Poor iron intake linked to inadequate diets, low iron intestinal absorption, chronic blood losses and increased requirements are common causes in high-income countries. © 2017 Elsevier Masson SAS. Tous droits réservés.

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.

PubMed

Martens, Lauren Herl; Zhang, Jiasheng; Barmada, Sami J; Zhou, Ping; Kamiya, Sherry; Sun, Binggui; Min, Sang-Won; Gan, Li; Finkbeiner, Steven; Huang, Eric J; Farese, Robert V

2012-11-01

Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn⁻/⁻) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn⁻/⁻ neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn⁻/⁻ mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn⁻/⁻ microglia treated with LPS/IFN-γ exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation.

Molecular defects leading to human complement component C6 deficiency in an African-American family

PubMed Central

Zhu, Z-B; Totemchokchyakarn, K; Atkinson, T P; Volanakis, J E

1998-01-01

Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis. The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection. By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations. The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual. Both mutations result in premature termination codons and C6 null alleles. Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father. PMID:9472666

NAD(P)H: Quinone Oxidoreductase 1 Deficiency Conjoint with Marginal Vitamin C Deficiency Causes Cigarette Smoke Induced Myelodysplastic Syndromes

PubMed Central

Das, Archita; Dey, Neekkan; Ghosh, Arunava; Das, Tanusree; Chatterjee, Indu B.

2011-01-01

Background The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. Methodology and Principal Findings Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. Conclusions and Significance CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS. PMID:21655231

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging.

PubMed

Tarantini, Stefano; Tucsek, Zsuzsanna; Valcarcel-Ares, M Noa; Toth, Peter; Gautam, Tripti; Giles, Cory B; Ballabh, Praveen; Wei, Jeanne Y; Wren, Jonathan D; Ashpole, Nicole M; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

2016-08-01

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1 f/f  + TBG-Cre-AAV8) by chronic infusion of angiotensin II. We found that circulating IGF-1 deficiency is associated with decreased microvascular density and exacerbates hypertension-induced microvascular rarefaction both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased

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'.

Treatment of Iron Deficiency in Women

PubMed Central

Breymann, C.; Römer, T.; Dudenhausen, J. W.

2013-01-01

Iron deficiency with and without anaemia is a common cause of morbidity, particularly in women. Iron deficiency is generally the result of an imbalance between iron loss and iron absorption. In women with symptoms suspicious for iron deficiency, it is important to confirm or exclude the suspicion using proper tests. The use of serum ferritin levels is considered the gold standard for diagnosis. Although the ideal ferritin levels are not unknown the current consent is that levels < 40 ng/ml indicate iron deficiency, which needs to be treated in symptomatic patients. However, symptoms can already occur at ferritin levels of < 100 ng/ml and treatment must be adapted to the individual patient. Iron supplementation is only indicated in symptomatic patients diagnosed with iron deficiency whose quality of life is affected. It is important to treat iron deficiency together with its causes or risk factors. For example, blood loss from hypermenorrhea should be reduced. Women also need to receive information about the benefits of an iron-rich diet. If oral treatment with iron supplements is ineffective, parenteral iron administration is recommended. PMID:26633902

High Prevalence of Vitamin D Deficiency in Cambodian Women: A Common Deficiency in a Sunny Country

PubMed Central

Smith, Geoffry; Wimalawansa, Sunil J.; Laillou, Arnaud; Sophonneary, Prak; Un, Samoeurn; Hong, Rathavuth; Poirot, Etienne; Kuong, Khov; Chamnan, Chhoun; De los Reyes, Francisco N.; Wieringa, Frank T.

2016-01-01

Recent studies have shown that in spite of being generally close to the equator; vitamin D deficiency is common in South East Asian countries. In order to quantify micronutrient status for women and children in Cambodia; a nationally-representative survey was conducted in 2014 linked to the Cambodian Demographic Health Survey. The countrywide median of 25(OH)D was, respectively, 64.9 and 91.1 nmol/L for mothers and children. Based on The Endocrine Society cutoffs (>50<75 nmol/L = insufficiency; ≤50 nmol/L = deficiency); 64.6% of mothers and 34.8% of their children had plasma vitamin D concentrations indicating insufficiency or deficiency. For deficiency alone, 29% of the mothers were found to be vitamin D deficient, but only 13.4% of children. Children who live in urban areas had a 43% higher rate of vitamin D insufficiency versus those who live in rural areas (OR; 1.434; 95% CI: 1.007; 2.041). However, such differences were not observed in their mothers. The high prevalence of vitamin D deficiency is likely in part due to lifestyle choices, including sun avoidance, increasingly predominant indoor work, and covered transport. These survey findings support the need for a broader national Cambodian study incorporating testing of adult men, adolescents and the elderly, and encompassing other parameters such as skeletal health. However, the data presented in this study already show significant deficiencies which need to be addressed and we discuss the benefit of establishing nationally-mandated food fortification programs to enhance the intake of vitamin D. PMID:27187456

Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers.

PubMed

Meier, Bettina; Volkova, Nadezda V; Hong, Ye; Schofield, Pieta; Campbell, Peter J; Gerstung, Moritz; Gartner, Anton

2018-05-01

Throughout their lifetime, cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. Although it is possible to associate mutational signatures extracted from human cancers with possible mutational processes, the exact causation is often unknown. Here, we use C. elegans genome sequencing of pms-2 and mlh-1 knockouts to reveal the mutational patterns linked to C. elegans MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit pole-4 Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the C. elegans MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and C. elegans MMR deficiency is the lack of elevated levels of N C G > NTG mutations in C. elegans, likely caused by the absence of cytosine (CpG) methylation in worms . The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes. © 2018 Meier et al.; Published by Cold Spring Harbor Laboratory Press.

Minimum Selenium Requirements Increase When Repleting Second-Generation Selenium-Deficient Rats but Are Not Further Altered by Vitamin E Deficiency.

PubMed

Sunde, Roger A; Thompson, Kevin M; Fritsche, Kevin L; Evenson, Jacqueline K

2017-05-01

Second-generation selenium-deficient weanling rats fed graded levels of dietary Se were used (a) to study the impact of initial Se deficiency on dietary Se requirements; (b) to determine if further decreases in selenoperoxidase expression, especially glutathione peroxidase 4 (Gpx4), affect growth or gross disease; and (c) to examine the impact of vitamin E deficiency on biochemical and molecular biomarkers of Se status. Rats were fed a vitamin E-deficient and Se-deficient crystalline amino acid diet (3 ng Se/g diet) or that diet supplemented with 100 μg/g all-rac-α-tocopheryl acetate and/or 0, 0.02, 0.05, 0.075, 0.1, or 0.2 μg Se/g diet as Na 2 SeO 3 for 28 days. Se-supplemented rats grew 6.91 g/day as compared to 2.17 and 3.87 g/day for vitamin E-deficient/Se-deficient and vitamin E-supplemented/Se-deficient groups, respectively. In Se-deficient rats, liver Se, plasma Gpx3, red blood cell Gpx1, liver Gpx1 and Gpx4 activities, and liver Gpx1 mRNA levels decreased to <1, <1, 21, 1.6, 49, and 11 %, respectively, of levels in rats fed 0.2 μg Se/g diet. For all biomarkers, ANOVA indicated significant effects of dietary Se, but no significant effects of vitamin E or vitamin E × Se interaction, showing that vitamin E deficiency, even in severely Se-deficient rat pups, does not result in compensatory changes in these biochemical and molecular biomarkers of selenoprotein expression. Se requirements determined in this study, however, were >50 % higher than in previous studies that started with Se-adequate rats, demonstrating that dietary Se requirements determined using initially Se-deficient animals can result in overestimation of Se requirements.

Prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Ouest and Sud-Est departments of Haiti.

PubMed

von Fricken, Michael E; Weppelmann, Thomas A; Eaton, Will T; Alam, Meer T; Carter, Tamar E; Schick, Laura; Masse, Roseline; Romain, Jean R; Okech, Bernard A

2014-07-01

Malaria remains a significant public health issue in Haiti, with chloroquine (CQ) used almost exclusively for the treatment of uncomplicated infections. Recently, single dose primaquine (PQ) was added to the Haitian national malaria treatment policy, despite a lack of information on the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency within the population. G6PD deficient individuals who take PQ are at risk of developing drug induced hemolysis (DIH). In this first study to examine G6PD deficiency rates in Haiti, 22.8% (range 14.9%-24.7%) of participants were found to be G6PD deficient (class I, II, or III) with 2.0% (16/800) of participants having severe deficiency (class I and II). Differences in deficiency were observed by gender, with males having a much higher prevalence of severe deficiency (4.3% vs. 0.4%) compared to females. Male participants were 1.6 times more likely to be classified as deficient and 10.6 times more likely to be classified as severely deficient compared to females, as expected. Finally, 10.6% (85/800) of the participants were considered to be at risk for DIH. Males also had much higher rates than females (19.3% vs. 4.6%) with 4.9 times greater likelihood (p value 0.000) of having an activity level that could lead to DIH. These findings provide useful information to policymakers and clinicians who are responsible for the implementation of PQ to control and manage malaria in Haiti. Copyright © 2014 Elsevier B.V. All rights reserved.

HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase.

PubMed

Ferdinandusse, Sacha; Waterham, Hans R; Heales, Simon J R; Brown, Garry K; Hargreaves, Iain P; Taanman, Jan-Willem; Gunny, Roxana; Abulhoul, Lara; Wanders, Ronald J A; Clayton, Peter T; Leonard, James V; Rahman, Shamima

2013-12-04

Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome. Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis. Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.

Autism and Folate Deficiency

DTIC Science & Technology

2010-05-01

social interaction that remains to be characterized more fully. Conclusion Ablation of genes in the folate pathway may result in abnormal adult...W81XWH-09-1-0246 TITLE: Autism and Folate Deficiency PRINCIPAL INVESTIGATOR: Richard H. Finnell, Ph.D...5a. CONTRACT NUMBER W81XWH-09-1-0246 Autism and Folate Deficiency 5b. GRANT NUMBER AR080064-Concept Award 5c. PROGRAM ELEMENT NUMBER

[Epidemic Vitamin D Deficiency in Prisoners Compared to the German Population: An Analysis Based on Laboratory Results].

PubMed

Pürner, Friedrich; Böhmer, Merle M; Wildner, Manfred

2018-04-20

Effects of long-term imprisonment on the vitamin D (vitD) status of prison inmates in Germany have not been systematically assessed so far. Special circumstances in prisons - little sunlight exposure combined with restricted outdoor activities - may lead to vitD deficiency among prisoners. The aim of this study was to assess the vitD status of prisoners and the general population in order to quantify the extent of vitD deficiency in both groups. VitD status (25(OH)D in blood serum samples) was assessed in female inmates of a prison in southern Germany between May 2012-June 2013. Suboptimal vitD status was defined as levels of 10-<20 µg/l, severe deficiency as<10 µg/l. A systematic literature search in PubMed was conducted in order to compare study results with vitD levels in the general population. Blood sera of 84 inmates (median age: 43 years; range: 19-75) were analyzed. Thirty women (36%) showed severe vitD deficiency, 47 (56%) suboptimal vitD levels. The literature search identified 10 studies which reported considerable vitD deficiency in the general population in Germany. VitD deficiency is very common in both prison inmates and the general population. Unlike prison inmates, the population is able to decide whether, when and how long they want to exposure to sunlight. Moreover, they can counteract deficiency via a nutrition rich in vitD. This is not possible for inmates. To prevent long-term effects of vitD deficiency, intake of vitD supplements during duration of imprisonment seems reasonable. © Georg Thieme Verlag KG Stuttgart · New York.

Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth

PubMed Central

Ono, Masanori; Yin, Ping; Navarro, Antonia; Moravek, Molly B.; Coon, John S.; Druschitz, Stacy A.; Gottardi, Cara J.; Bulun, Serdar E.

2014-01-01

Objective Dysregulation of WNT signaling plays a central role in tumor cell growth and progression. Our goal was to assess the effect of three WNT/β-catenin pathway inhibitors, Inhibitor of β-Catenin And TCF4 (ICAT), niclosamide, and XAV939 on the proliferation of primary cultures of human uterine leiomyoma cells. Design Prospective study of human leiomyoma cells obtained from myomectomy or hysterectomy. Setting University research laboratory. Patient(s) Women (n=38) aged 27–53 years undergoing surgery. Intervention(s) Adenoviral ICAT overexpression or treatment with varying concentrations of niclosamide or XAV939. Main Outcome Measure(s) Cell proliferation, cell death, WNT/β-catenin target gene expression or reporter gene regulation, β-catenin levels and cellular localization. Result(s) ICAT, niclosamide, or XAV939 inhibit WNT/β-catenin pathway activation and exert anti-proliferative effects in primary cultures of human leiomyoma cells. Conclusion(s) Three WNT/β-catenin pathway inhibitors specifically block human leiomyoma growth and proliferation, suggesting that the canonical WNT pathway may be a potential therapeutic target for the treatment of uterine leiomyoma. Our findings provide rationale for further preclinical and clinical evaluation of ICAT, niclosamide, and XAV939 as candidate anti-tumor agents for uterine leiomyoma. PMID:24534281

The treatment of iron deficiency without anaemia (in otherwise healthy persons).

PubMed

Clénin, German E

2017-06-21

Iron deficiency is the most widespread and frequent nutritional disorder in the world. It affects a high proportion of children and women in developing countries and is also significantly prevalent in the industrialised world, with a clear predominance in adolescents and menstruating females. Iron is essential for optimal cognitive function and physical performance, not only as a binding site of oxygen but also as a critical constituent of many enzymes. Therefore iron deficiency at all its levels - nonanaemic iron deficiency, iron deficiency with microcytosis or hypochromia and iron deficiency anaemia - should be treated. In the presence of normal stores, however, preventative iron administration is inefficient, has side effects and seems to be harmful. In symptomatic patients with fatigue or in a population at risk for iron deficiency (adolescence, heavy or prolonged menstruation, high performance sport, vegetarian or vegan diet, eating disorder, underweight), a baseline set of blood tests including haemoglobin concentration, haematocrit, mean cellular volume, mean cellular haemoglobin, percentage of hypochromic erythrocytes and serum ferritin levels are important to monitor iron deficiency. To avoid false negative results (high ferritin levels in spite of iron deficiency), an acute phase reaction should be excluded by history and measurement of C-reactive protein. An algorithm leads through this diagnostic process and the decision making for a possible treatment. For healthy males and females aged >15 years, a ferritin cut-off of 30 µg/l is appropriate. For children from 6-12 years and younger adolescents from 12-15 years, cut-offs of 15 and 20 µg/l, respectively, are recommended. As a first step in treatment, counselling and oral iron therapy are usually combined. Integrating haem and free iron regularly into the diet, looking for enhancers and avoiding inhibitors of iron uptake is beneficial. In order to prevent reduced compliance, mainly as a result of

Vitamin D deficiency is associated with orthostatic hypotension in oldest-old women.

PubMed

Annweiler, C; Schott, A-M; Rolland, Y; Beauchet, O

2014-09-01

Orthostatic hypotension, a condition that mostly affects 'oldest-old' (i.e. ≥80 years) adults, is primarily explained by age-related dysfunction of blood pressure control. Vitamin D may contribute to blood pressure control. The aim of this study was to determine whether vitamin D deficiency is associated with orthostatic hypotension in oldest-old adults. Cross-sectional analysis at baseline of the EPIDOS study. Five French areas. A total of 329 community-dwelling oldest-old women (mean age 83.3 ± 0.2 years). Orthostatic hypotension was defined as a systolic blood pressure drop of ≥20 mmHg and/or a diastolic blood pressure drop of ≥10 mmHg within 3 min of standing. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25OHD) concentration ≤10 ng mL(-1) . Covariates included in the models were age, body mass index, diabetes mellitus, supine mean arterial pressure, number of drugs taken per day, use of antihypertensive or psychoactive drugs, cognition, quadriceps strength, current smoking, alcohol consumption, serum concentrations of parathyroid hormone, calcium and creatinine and season of testing. Diastolic orthostatic hypotension was observed more often among women with vitamin D deficiency (19.2%) compared to those without (10.0%; P = 0.03). There was an inverse linear association between 25OHD concentration and change in diastolic blood pressure after 3 min of standing (adjusted β = -0.07, P = 0.046). Similarly, 25OHD deficiency was associated with orthostatic hypotension [adjusted odds ratio (OR) 3.36, P = 0.004], specifically with diastolic orthostatic hypotension (adjusted OR 3.81, P = 0.003). 25OHD deficiency was associated with orthostatic hypotension in oldest-old women, due to a greater drop in diastolic blood pressure on standing. This finding may lead to better understanding of the pathophysiology of falls in oldest-old adults with vitamin D deficiency. © 2014 The Association for the Publication of the Journal of

Vitamin A deficiency in Bangladesh: a review and recommendations for improvement.

PubMed

Ahmed, F

1999-03-01

This article provides a comprehensive review of the change in vitamin A status and the extent of vitamin A deficiency among different population groups in Bangladesh up to the present time. The result of experience with different strategies and interventions designed to improve vitamin A status are then reviewed, leading to a discussion of key options for action, as well as important areas for research and evaluation. All the available data have been examined in detail, including data from nationally representative samples and nationwide surveys, as well as small studies in different population groups. Reports on the effectiveness of different intervention programmes have been used. Over the past three decades a number of studies, which include national nutrition surveys, have been carried out to investigate the prevalence of vitamin A deficiency among different population groups in Bangladesh, and they have demonstrated a significant public health problem. Studies have shown that the prevalence of severe deficiency, based on the prevalence of night blindness in preschool children, decreased from 3.6% in 1982-83 to 1.78% in 1989 and 0.6% in 1996. However, there is still a high prevalence of subclinical vitamin A deficiency, based on the biochemical assessment of serum retinol levels in preschool children, estimated mainly from hospital-based groups. Night blindness and Bitot's spot are also found to exist among school-age children and adolescents. Recent reports indicate that night blindness among rural mothers is as high as 1.4%. Only a limited number of studies, with small sample sizes, are available where serum retinol has been reported for school-age children, adolescents and pregnant women. Nevertheless, these studies confirm the presence of low levels of serum retinol and hence, the existence of subclinical vitamin A deficiency. Furthermore, the dietary intake of vitamin A in each population group has been found to be less than the Recommended Daily Allowance

Kinetics and thermodynamics of exonuclease-deficient DNA polymerases

NASA Astrophysics Data System (ADS)

Gaspard, Pierre

2016-04-01

A kinetic theory is developed for exonuclease-deficient DNA polymerases, based on the experimental observation that the rates depend not only on the newly incorporated nucleotide, but also on the previous one, leading to the growth of Markovian DNA sequences from a Bernoullian template. The dependencies on nucleotide concentrations and template sequence are explicitly taken into account. In this framework, the kinetic and thermodynamic properties of DNA replication, in particular, the mean growth velocity, the error probability, and the entropy production are calculated analytically in terms of the rate constants and the concentrations. Theory is compared with numerical simulations for the DNA polymerases of T7 viruses and human mitochondria.

SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity.

PubMed

Chen, Yingjia; Hu, Fanlei; Dong, Xuejiao; Zhao, Meng; Wang, Jing; Sun, Xiaolin; Kim, Tae Jin; Li, Zhanguo; Liu, Wanli

2017-11-01

Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d fl/fl Aicda Cre/+ mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID + B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d fl/fl Aicda Cre/+ mouse model shows B cell-dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d fl/fl mice, but not from the Innp5d fl/fl Aicda Cre/+ mice. This finding highlights the importance of defective B10 cells in Innp5d fl/fl Aicda Cre/+ mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d fl/fl Aicda Cre/+ mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

30 CFR 57.8527 - Oxygen-deficiency testing.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Oxygen-deficiency testing. 57.8527 Section 57... Underground Only § 57.8527 Oxygen-deficiency testing. Flame safety lamps or other suitable devices shall be used to test for acute oxygen deficiency. ...

30 CFR 57.8527 - Oxygen-deficiency testing.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Oxygen-deficiency testing. 57.8527 Section 57... Underground Only § 57.8527 Oxygen-deficiency testing. Flame safety lamps or other suitable devices shall be used to test for acute oxygen deficiency. ...

30 CFR 57.8527 - Oxygen-deficiency testing.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Oxygen-deficiency testing. 57.8527 Section 57... Underground Only § 57.8527 Oxygen-deficiency testing. Flame safety lamps or other suitable devices shall be used to test for acute oxygen deficiency. ...

30 CFR 57.8527 - Oxygen-deficiency testing.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Oxygen-deficiency testing. 57.8527 Section 57... Underground Only § 57.8527 Oxygen-deficiency testing. Flame safety lamps or other suitable devices shall be used to test for acute oxygen deficiency. ...

30 CFR 57.8527 - Oxygen-deficiency testing.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Oxygen-deficiency testing. 57.8527 Section 57... Underground Only § 57.8527 Oxygen-deficiency testing. Flame safety lamps or other suitable devices shall be used to test for acute oxygen deficiency. ...

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.

PubMed

Chen, Ina; Mathews-Greiner, Lesley; Li, Dandan; Abisoye-Ogunniyan, Abisola; Ray, Satyajit; Bian, Yansong; Shukla, Vivek; Zhang, Xiaohu; Guha, Raj; Thomas, Craig; Gryder, Berkley; Zacharia, Athina; Beane, Joal D; Ravichandran, Sarangan; Ferrer, Marc; Rudloff, Udo

2017-05-01

delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

Niemann-Pick Type C1 deficiency in microglia does not cause neuron death in vitro.

PubMed

Peake, Kyle B; Campenot, Robert B; Vance, Dennis E; Vance, Jean E

2011-09-01

Niemann-Pick Type C (NPC) disease is an autosomal recessive disorder that results in accumulation of cholesterol and other lipids in late endosomes/lysosomes and leads to progressive neurodegeneration and premature death. The mechanism by which lipid accumulation causes neurodegeneration remains unclear. Inappropriate activation of microglia, the resident immune cells of the central nervous system, has been implicated in several neurodegenerative disorders including NPC disease. Immunohistochemical analysis demonstrates that NPC1 deficiency in mouse brains alters microglial morphology and increases the number of microglia. In primary cultures of microglia from Npc1(-/-) mice cholesterol is sequestered intracellularly, as occurs in other NPC-deficient cells. Activated microglia secrete potentially neurotoxic molecules such as tumor necrosis factor-α (TNFα). However, NPC1 deficiency in isolated microglia did not increase TNFα mRNA or TNFα secretion in vitro. In addition, qPCR analysis shows that expression of pro-inflammatory and oxidative stress genes is the same in Npc1(+/+) and Npc1(-/-) microglia, whereas the mRNA encoding the anti-inflammatory cytokine, interleukin-10 in Npc1(-/-) microglia is ~60% lower than in Npc1(+/+) microglia. The survival of cultured neurons was not impaired by NPC1 deficiency, nor was death of Npc1(-/-) and Npc1(+/+) neurons in microglia-neuron co-cultures increased by NPC1 deficiency in microglia. However, a high concentration of Npc1(-/-) microglia appeared to promote neuron survival. Thus, although microglia exhibit an active morphology in NPC1-deficient brains, lack of NPC1 in microglia does not promote neuron death in vitro in microglia-neuron co-cultures, supporting the view that microglial NPC1 deficiency is not the primary cause of neuron death in NPC disease. Copyright © 2011 Elsevier B.V. All rights reserved.

The "multiple hormone deficiency" theory of aging: is human senescence caused mainly by multiple hormone deficiencies?

PubMed

Hertoghe, T

2005-12-01

In the human body, the productions, levels and cell receptors of most hormones progressively decline with age, gradually putting the body into various states of endocrine deficiency. The circadian cycles of these hormones also change, sometimes profoundly, with time. In aging individuals, the well-balanced endocrine system can fall into a chaotic condition with losses, phase-advancements, phase delays, unpredictable irregularities of nycthemeral hormone cycles, in particular in very old or sick individuals. The desynchronization makes hormone activities peak at the wrong times and become inefficient, and in certain cases health threatening. The occurrence of multiple hormone deficits and spilling through desynchronization may constitute the major causes of human senescence, and they are treatable causes. Several arguments can be put forward to support the view that senescence is mainly a multiple hormone deficiency syndrome: First, many if not most of the signs, symptoms and diseases (including cardiovascular diseases, cancer, obesity, diabetes, osteoporosis, dementia) of senescence are similar to physical consequences of hormone deficiencies and may be caused by hormone deficiencies. Second, most of the presumed causes of senescence such as excessive free radical formation, glycation, cross-linking of proteins, imbalanced apoptosis system, accumulation of waste products, failure of repair systems, deficient immune system, may be caused or favored by hormone deficiencies. Even genetic causes such as limits to cell proliferation (such as the Hayflick limit of cell division), poor gene polymorphisms, premature telomere shortening and activation of possible genetic "dead programs" may have links with hormone deficiencies, being either the consequence, the cause, or the major favoring factor of hormone deficiencies. Third, well-dosed and -balanced hormone supplements may slow down or stop the progression of signs, symptoms, or diseases of senescence and may often

Hematopoietic studies in vitamin A deficiency.

PubMed

Hodges, R E; Sauberlich, H E; Canham, J E; Wallace, D L; Rucker, R B; Mejia, L A; Mohanram, M

1978-05-01

Recent studies of experimental vitamin A deficiency in man led the authors to conclude that anemia may result from lack of vitamin A. A review of numerous nutrition surveys in underdeveloped countries enhanced the suspicion that deficiency of vitamin A does contribute to the prevalence of anemia. Preliminary studies of vitamin A-deficient rats confirmed previous observations that anemia may result from lack of this vitamin. The livers of these animals had very low concentrations of vitamin A but normal or increased concentrations of iron. The finding of anemia is in contrast with other reports that vitamin A deficiency may cause elevated values for hemoglobin and hematocrit. The authors suggest that loss of taste and smell as a result of deficiency may account for refusal of experimental animals to eat and drink enough to prevent inanitation and dehydration. The resulting hemoconcentration may mask the true hematological picture, which is one of anemia.

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.

[Immune, inflammatory, and nutritional protein profile in children with iron deficiency in Côte d'Ivoire].

PubMed

Yapi, Houphouët Félix; Ahiboh, Hugues; Yayo, Eric; Edjeme, Angele; Attoungbre-Hauhouot, Marie Laure; Allico, Joseph Djaman; Monnet, Dagui

2009-01-01

not differ significantly. The reduced IgG associated with iron deficiency may be attributed to the role that iron plays in the proliferation and maturation of lymphocytes. Reduced iron levels would thus lead to slowing down the hematopoietic mechanism, resulting in a decrease in B lymphocyte production and thus inevitably a reduction in IgG synthesis. The reduction in albumin and TBPA associated with the iron deficiency but in the absence of any sign of malnutrition (W/H > 96%) or inflammatory risk (PINI < 2) in either study group shows that iron may play a dominant role during protein synthesis. Iron deficiency might limit the energy of cellular tissues, leading to a reduction in RNA activity (transcription and translation), which would in turn decrease ribosome activity in tissues and thus reduce amino acid synthesis in cells, resulting in the reduction observed in protein synthesis. The lack of difference between the study groups in inflammatory proteins, notably CRP and alpha1-GPA, indicates that iron deficiency does not appear to be related to an inflammatory process. This study of children without any apparent clinical signs of iron deficiency shows that such a deficiency may be associated with a disruption in protein production. The proteins concerned include IgG, TBPA and albumin. The public authorities should pay particular attention to improving children's diets, especially their micronutrient levels, including for iron, vitamin A and zinc.

Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis

PubMed Central

Sun, Yang; Zhang, Erik; Lao, Taotao; Pereira, Ana M.; Li, Chenggang; Xiong, Li; Morrison, Tasha; Haley, Kathleen J.; Zhou, Xiaobo; Yu, Jane J.

2014-01-01

Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promote metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Akt and ERK1/2, induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species, and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology, and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of TSC2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers. PMID

Neonatal growth restriction-related leptin deficiency enhances leptin-triggered sympathetic activation and central angiotensin II receptor-dependent stress-evoked hypertension.

PubMed

Peotta, Veronica; Rahmouni, Kamal; Segar, Jeffrey L; Morgan, Donald A; Pitz, Kate M; Rice, Olivia M; Roghair, Robert D

2016-08-01

Neonatal growth restriction (nGR) leads to leptin deficiency and increases the risk of hypertension. Previous studies have shown nGR-related hypertension is normalized by neonatal leptin (nLep) and exacerbated by psychological stress. With recent studies linking leptin and angiotensin signaling, we hypothesized that nGR-induced nLep deficiency increases adult leptin sensitivity; leading to leptin- or stress-induced hypertension, through a pathway involving central angiotensin II type 1 receptors. We randomized mice with incipient nGR, by virtue of their presence in large litters, to vehicle or physiologic nLep supplementation (80 ng/g/d). Adult caloric intake and arterial pressure were monitored at baseline, during intracerebroventricular losartan infusion and during systemic leptin administration. nGR increased leptin-triggered renal sympathetic activation and hypertension with increased leptin receptor expression in the arcuate nucleus of the hypothalamus; all of those nGR-associated phenotypes were normalized by nLep. nGR mice also had stress-related hyperphagia and hypertension, but only the stress hypertension was blocked by central losartan infusion. nGR leads to stress hypertension through a pathway that involves central angiotensin II receptors, and nGR-associated leptin deficiency increases leptin-triggered hypertension in adulthood. These data suggest potential roles for preservation of neonatal growth and nLep supplementation in the prevention of nGR-related hypertension.

14 CFR 63.19 - Operations during physical deficiency.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Operations during physical deficiency. 63... physical deficiency. No person may serve as a flight engineer or flight navigator during a period of known physical deficiency, or increase in physical deficiency, that would make him unable to meet the physical...

14 CFR 63.19 - Operations during physical deficiency.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Operations during physical deficiency. 63... physical deficiency. No person may serve as a flight engineer or flight navigator during a period of known physical deficiency, or increase in physical deficiency, that would make him unable to meet the physical...

14 CFR 63.19 - Operations during physical deficiency.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Operations during physical deficiency. 63... physical deficiency. No person may serve as a flight engineer or flight navigator during a period of known physical deficiency, or increase in physical deficiency, that would make him unable to meet the physical...

14 CFR 63.19 - Operations during physical deficiency.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Operations during physical deficiency. 63... physical deficiency. No person may serve as a flight engineer or flight navigator during a period of known physical deficiency, or increase in physical deficiency, that would make him unable to meet the physical...

14 CFR 63.19 - Operations during physical deficiency.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Operations during physical deficiency. 63... physical deficiency. No person may serve as a flight engineer or flight navigator during a period of known physical deficiency, or increase in physical deficiency, that would make him unable to meet the physical...

Folate deficiency

MedlinePlus

... as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole) Eating an unhealthy diet that does not include enough fruits and vegetables Kidney dialysis Symptoms Folic acid deficiency may cause: Fatigue, irritability, or diarrhea Poor growth Smooth and ...

Mitochondrial deficiency impairs hypoxic induction of HIF-1 transcriptional activity and retards tumor growth

PubMed Central

Koido, Masaru; Haga, Naomi; Furuno, Aki; Tsukahara, Satomi; Sakurai, Junko; Tani, Yuri; Sato, Shigeo; Tomida, Akihiro

2017-01-01

Mitochondria can be involved in regulating cellular stress response to hypoxia and tumor growth, but little is known about that mechanistic relationship. Here, we show that mitochondrial deficiency severely retards tumor xenograft growth with impairing hypoxic induction of HIF-1 transcriptional activity. Using mtDNA-deficient ρ0 cells, we found that HIF-1 pathway activation was comparable in slow-growing ρ0 xenografts and rapid-growing parental xenografts. Interestingly, we found that ex vivo ρ0 cells derived from ρ0 xenografts exhibited slightly increased HIF-1α expression and modest HIF-1 pathway activation regardless of oxygen concentration. Surprisingly, ρ0 cells, as well as parental cells treated with oxidative phosphorylation inhibitors, were unable to boost HIF-1 transcriptional activity during hypoxia, although HIF-1α protein levels were ordinarily increased in these cells under hypoxic conditions. These findings indicate that mitochondrial deficiency causes loss of hypoxia-induced HIF-1 transcriptional activity and thereby might lead to a constitutive HIF-1 pathway activation as a cellular adaptation mechanism in tumor microenvironment. PMID:28060746

Relationship of vitamin A deficiency, iron deficiency, and inflammation to anemia among preschool children in the Republic of the Marshall Islands.

PubMed

Gamble, M V; Palafox, N A; Dancheck, B; Ricks, M O; Briand, K; Semba, R D

2004-10-01

Although vitamin A deficiency, iron deficiency, and inflammation may contribute to anemia, their relative contribution to anemia has not been well characterized in preschool children in developing countries. To characterize the contributions of vitamin A and iron deficiencies and inflammation to anemia among preschool children in the Republic of the Marshall Islands. A community-based survey, the Republic of the Marshall Islands Vitamin A Deficiency Study, was conducted among 919 preschool children. The relationship of vitamin A and iron status and markers of inflammation, tumor necrosis factor-alpha, alpha1-acid glycoprotein, and interleukin-10, to anemia were studied in a subsample of 367 children. Among the 367 children, the prevalence of anemia was 42.5%. The prevalence of severe vitamin A deficiency (serum vitamin A < 0.35 micromol/l) and iron deficiency (serum ferritin < 12 microg/dl) were 10.9 and 51.7%, respectively. The respective prevalence of iron deficiency anemia (hemoglobin < 110 g/l and iron deficiency), anemia with inflammation (anemia with TNF-alpha > 2 pg/ml and/or AGP > 1000 mg/l), and severe vitamin A deficiency combined with anemia was 26.7, 35.6, and 7.6%. In multivariate linear regression models that adjusted for age, sex, and inflammation, both iron deficiency (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.08-2.83, P = 0.023) and severe vitamin A deficiency (OR 4.85, 95% CI 2.14-10.9, P < 0.0001) were significantly associated with anemia. Both iron and vitamin A deficiencies were independent risk factors for anemia, but inflammation was not a significant risk factor for anemia among these preschool children.

Growth hormone deficiency: an update.

PubMed

Audí, L; Fernández-Cancio, M; Camats, N; Carrascosa, A

2013-03-01

Growth hormone (GH) deficiency (GHD) in humans manifests differently according to the individual developmental stage (early after birth, during childhood, at puberty or in adulthood), the cause or mechanism (genetic, acquired or idiopathic), deficiency intensity and whether it is the only pituitary-affected hormone or is combined with that of other pituitary hormones or forms part of a complex syndrome. Growing knowledge of the genetic basis of GH deficiency continues to provide us with useful information to further characterise mutation types and mechanisms for previously described and new candidate genes. Despite these advances, a high proportion of GH deficiencies with no recognisable acquired basis continue to be labelled as idiopathic, although less frequently when they are congenital and/or familial. The clinical and biochemical diagnoses continue to be a conundrum despite efforts to harmonise biochemical assays for GH and IGF-1 analysis, probably because the diagnosis based on the so-called GH secretion stimulation tests will prove to be of limited usefulness for predicting therapy indications.

Management of Iron Deficiency Anemia

PubMed Central

Jimenez, Kristine; Kulnigg-Dabsch, Stefanie

2015-01-01

Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks. PMID:27099596

[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.

Iron Deficiency Anemia: Focus on Infectious Diseases in Lesser Developed Countries

PubMed Central

Shaw, Julia G.; Friedman, Jennifer F.

2011-01-01

Iron deficiency anemia is thought to affect the health of more than one billion people worldwide, with the greatest burden of disease experienced in lesser developed countries, particularly women of reproductive age and children. This greater disease burden is due to both nutritional and infectious etiologies. Individuals in lesser developed countries have diets that are much lower in iron, less access to multivitamins for young children and pregnant women, and increased rates of fertility which increase demands for iron through the life course. Infectious diseases, particularly parasitic diseases, also lead to both extracorporeal iron loss and anemia of inflammation, which decreases bioavailability of iron to host tissues. This paper will address the unique etiologies and consequences of both iron deficiency anemia and the alterations in iron absorption and distribution seen in the context of anemia of inflammation. Implications for diagnosis and treatment in this unique context will also be discussed. PMID:21738863

Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency.

PubMed

Guerriero, Réjean M; Patel, Archana A; Walsh, Brian; Baumer, Fiona M; Shah, Ankoor S; Peters, Jurriaan M; Rodan, Lance H; Agrawal, Pankaj B; Pearl, Phillip L; Takeoka, Masanori

2017-11-01

Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5'-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5'-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5'-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5'-phosphate oxidase deficiency. A series of six patients with homozygous mutations of PNPO, the gene coding pyridox(am)ine 5'-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5'-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.

PubMed

Jenkins, Dagan; Bitner-Glindzicz, Maria; Malcolm, Sue; Hu, Chih-Chi A; Allison, Jennifer; Winyard, Paul J D; Gullett, Ambrose M; Thomas, David F M; Belk, Rachel A; Feather, Sally A; Sun, Tung-Tien; Woolf, Adrian S

2005-07-01

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.

CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome.

PubMed

Luna-Sánchez, Marta; Hidalgo-Gutiérrez, Agustín; Hildebrandt, Tatjana M; Chaves-Serrano, Julio; Barriocanal-Casado, Eliana; Santos-Fandila, Ángela; Romero, Miguel; Sayed, Ramy Ka; Duarte, Juan; Prokisch, Holger; Schuelke, Markus; Distelmaier, Felix; Escames, Germaine; Acuña-Castroviejo, Darío; López, Luis C

2017-01-01

Coenzyme Q (CoQ) is a key component of the mitochondrial respiratory chain, but it also has several other functions in the cellular metabolism. One of them is to function as an electron carrier in the reaction catalyzed by sulfide:quinone oxidoreductase (SQR), which catalyzes the first reaction in the hydrogen sulfide oxidation pathway. Therefore, SQR may be affected by CoQ deficiency. Using human skin fibroblasts and two mouse models with primary CoQ deficiency, we demonstrate that severe CoQ deficiency causes a reduction in SQR levels and activity, which leads to an alteration of mitochondrial sulfide metabolism. In cerebrum of Coq9 R239X mice, the deficit in SQR induces an increase in thiosulfate sulfurtransferase and sulfite oxidase, as well as modifications in the levels of thiols. As a result, biosynthetic pathways of glutamate, serotonin, and catecholamines were altered in the cerebrum, and the blood pressure was reduced. Therefore, this study reveals the reduction in SQR activity as one of the pathomechanisms associated with CoQ deficiency syndrome. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Glucose-6-phosphate dehydrogenase deficiency and reduced haemoglobin levels in African children with severe malaria.

PubMed

Nguetse, Christian N; Meyer, Christian G; Adegnika, Ayola Akim; Agbenyega, Tsiri; Ogutu, Bernhards R; Kremsner, Peter G; Velavan, Thirumalaisamy P

2016-07-07

Extensive studies investigating the role of host genetic factors during malaria associate glucose-6-phosphate dehydrogenase deficiency with relative protection. G6PD deficiency had been reported to associate with anti-malarial drug induced with haemolytic anaemia. A total of 301 Gabonese, Ghanaian, and Kenyan children aged 6-120 months with severe malaria recruited in a multicentre trial on artesunate were included in this sub-study. G6PD normal (type B), heterozygous (type A(+)) and deficient (type A(-)) genotypes were determined by direct sequencing of the common African mutations G202A and A376G. Furthermore, multivariate analyses were executed to associate possible contributions of G6PD deficiency with baseline haemoglobin levels, parasitaemia and with severe malarial anaemia. Two hundred and seventy-eight children (132 females and 146 males) were successfully genotyped for G6PD variants. The overall prevalence of G6PD deficiency was 13 % [36/278; 3 % (4/132) female homozygous and 22 % (32/146) male hemizygous], 14 % (40/278) children were female heterozygous while 73 % (202/278) were G6PD normal [67 % (88/132) females and 78 % (114/146) males] individuals. Multivariate regression revealed a significant association of moderately and severely deficient G6PD genotypes with haemoglobin levels according to the baseline data (p < 0.0001; G6PD heterozygous: p < 0.0001; G6PD deficient: p = 0.009), but not with severe malarial anaemia (p = 0.66). No association of G6PD genotypes with baseline parasitaemia. In this study, moderately (type A(+)) and severely (type A(-)) G6PD deficiency showed significant association with lower haemoglobin concentrations at baseline in African children with severe malaria without leading to severe malarial anaemia. In addition, there was no association of G6PD variant types with parasite densities on admission.

Iron deficiency: new insights into diagnosis and treatment.

PubMed

Camaschella, Clara

2015-01-01

Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children and young women. In developing countries, iron deficiency is caused by poor iron intake and/or parasitic infection, whereas vegetarian dietary choices, poor iron absorption, and chronic blood loss are common causes in high-income countries. Erythropoiesis stimulating agents can result in functional iron deficiency for erythropoiesis even when stores are iron-replete. Diagnosis of iron deficiency is straightforward, except when it occurs in the context of inflammatory disorders. Oral iron salts correct absolute iron deficiency in most patients, because low hepcidin levels facilitate iron absorption. Unfortunately frequent side effects limit oral iron efficacy. Intravenous iron is increasingly utilized, because currently available preparations allow rapid normalization of total body iron even with a single infusion and are effective also in functional iron deficiency and in iron deficiency associated with inflammatory disorders. The evidence is accumulating that these preparations are safe and effective. However, long-term safety issues of high doses of iron need to be further explored. © 2015 by The American Society of Hematology. All rights reserved.

46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency.

PubMed

Mendonca, Berenice B; Gomes, Nathalia Lisboa; Costa, Elaine M F; Inacio, Marlene; Martin, Regina M; Nishi, Mirian Y; Carvalho, Filomena Marino; Tibor, Francisco Denes; Domenice, Sorahia

2017-01-01

17β-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17β-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17β-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5α-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17β-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the previously reported cases of 17β-HSD3 deficiency adding our own cases. Copyright © 2016. Published by Elsevier Ltd.

Unchanged mitochondrial organization and compartmentation of high-energy phosphates in creatine-deficient GAMT−/− mouse hearts

PubMed Central

Branovets, Jelena; Sepp, Mervi; Kotlyarova, Svetlana; Jepihhina, Natalja; Sokolova, Niina; Aksentijevic, Dunja; Lygate, Craig A.; Neubauer, Stefan; Birkedal, Rikke

2013-01-01

Disruption of the creatine kinase (CK) system in hearts of CK-deficient mice leads to changes in the ultrastructure and regulation of mitochondrial respiration. We expected to see similar changes in creatine-deficient mice, which lack the enzyme guanidinoacetate methyltransferase (GAMT) to produce creatine. The aim of this study was to characterize the changes in cardiomyocyte mitochondrial organization, regulation of respiration, and intracellular compartmentation associated with GAMT deficiency. Three-dimensional mitochondrial organization was assessed by confocal microscopy. On populations of permeabilized cardiomyocytes, we recorded ADP and ATP kinetics of respiration, competition between mitochondria and pyruvate kinase for ADP produced by ATPases, ADP kinetics of endogenous pyruvate kinase, and ATP kinetics of ATPases. These data were analyzed by mathematical models to estimate intracellular compartmentation. Quantitative analysis of morphological and kinetic data as well as derived model fits showed no difference between GAMT-deficient and wild-type mice. We conclude that inactivation of the CK system by GAMT deficiency does not alter mitochondrial organization and intracellular compartmentation in relaxed cardiomyocytes. Thus, our results suggest that the healthy heart is able to preserve cardiac function at a basal level in the absence of CK-facilitated energy transfer without compromising intracellular organization and the regulation of mitochondrial energy homeostasis. This raises questions on the importance of the CK system as a spatial energy buffer in unstressed cardiomyocytes. PMID:23792673

33 CFR 72.01-30 - Temporary deficiencies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Temporary deficiencies. 72.01-30 Section 72.01-30 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY AIDS TO NAVIGATION MARINE INFORMATION Notices to Mariners § 72.01-30 Temporary deficiencies. Temporary deficiencies...

33 CFR 72.01-30 - Temporary deficiencies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Temporary deficiencies. 72.01-30 Section 72.01-30 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY AIDS TO NAVIGATION MARINE INFORMATION Notices to Mariners § 72.01-30 Temporary deficiencies. Temporary deficiencies...

Inbred Strain-Specific Effects of Exercise in Wild Type and Biglycan Deficient Mice

PubMed Central

Wallace, Joseph M.; Golcuk, Kurtulus; Morris, Michael D.; Kohn, David H.

2010-01-01

Biglycan (bgn)-deficient mice (KO) have defective osteoblasts which lead to changes in the amount and quality of bone. Altered tissue strength in C57BL6/129 (B6;129) KO mice, a property which is independent of tissue quantity, suggests that deficiencies in tissue quality are responsible. However, the response to bgn-deficiency is inbred strain-specific. Mechanical loading influences bone matrix quality in addition to any increase in bone mass or change in bone formation activity. Since many diseases influence the mechanical integrity of bone through altered tissue quality, loading may be a way to prevent and treat extracellular matrix deficiencies. C3H/He (C3H) mice consistently have a less vigorous response to mechanical loading vs. other inbred strains. It was therefore hypothesized that the bones from both wild type (WT) and KO B6;129 mice would be more responsive to exercise than the bones from C3H mice. To test these hypotheses at 11 weeks of age, following 21 consecutive days of exercise, we investigated cross-sectional geometry, mechanical properties, and tissue composition in the tibiae of male mice bred on B6;129 and C3H backgrounds. This study demonstrated inbred strain-specific compositional and mechanical changes following exercise in WT and KO mice, and showed evidence of genotype-specific changes in bone in response to loading in a gene disruption model. This study further shows that exercise can influence bone tissue composition and/or mechanical integrity without changes in bone geometry. Together, these data suggest that exercise may represent a possible means to alter tissue quality and mechanical deficiencies caused by many diseases of bone. PMID:20033775

Atrophy and neuron loss: effects of a protein-deficient diet on sympathetic neurons.

PubMed

Gomes, Silvio Pires; Nyengaard, Jens Randel; Misawa, Rúbia; Girotti, Priscila Azevedo; Castelucci, Patrìcia; Blazquez, Francisco Hernandez Javier; de Melo, Mariana Pereira; Ribeiro, Antonio Augusto Coppi

2009-12-01

Protein deficiency is one of the biggest public health problems in the world, accounting for about 30-40% of hospital admissions in developing countries. Nutritional deficiencies lead to alterations in the peripheral nervous system and in the digestive system. Most studies have focused on the effects of protein-deficient diets on the enteric neurons, but not on sympathetic ganglia, which supply extrinsic sympathetic input to the digestive system. Hence, in this study, we investigated whether a protein-restricted diet would affect the quantitative structure of rat coeliac ganglion neurons. Five male Wistar rats (undernourished group) were given a pre- and postnatal hypoproteinic diet receiving 5% casein, whereas the nourished group (n = 5) was fed with 20% casein (normoproteinic diet). Blood tests were carried out on the animals, e.g., glucose, leptin, and triglyceride plasma concentrations. The main structural findings in this study were that a protein-deficient diet (5% casein) caused coeliac ganglion (78%) and coeliac ganglion neurons (24%) to atrophy and led to neuron loss (63%). Therefore, the fall in the total number of coeliac ganglion neurons in protein-restricted rats contrasts strongly with no neuron losses previously described for the enteric neurons of animals subjected to similar protein-restriction diets. Discrepancies between our figures and the data for enteric neurons (using very similar protein-restriction protocols) may be attributable to the counting method used. In light of this, further systematic investigations comparing 2-D and 3-D quantitative methods are warranted to provide even more advanced data on the effects that a protein-deficient diet may exert on sympathetic neurons. (c) 2009 Wiley-Liss, Inc. Copyright 2009 Wiley-Liss, Inc.

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

PubMed

Musumeci, Lucia; Kuijpers, Marijke J; Gilio, Karen; Hego, Alexandre; Théâtre, Emilie; Maurissen, Lisbeth; Vandereyken, Maud; Diogo, Catia V; Lecut, Christelle; Guilmain, William; Bobkova, Ekaterina V; Eble, Johannes A; Dahl, Russell; Drion, Pierre; Rascon, Justin; Mostofi, Yalda; Yuan, Hongbin; Sergienko, Eduard; Chung, Thomas D Y; Thiry, Marc; Senis, Yotis; Moutschen, Michel; Mustelin, Tomas; Lancellotti, Patrizio; Heemskerk, Johan W M; Tautz, Lutz; Oury, Cécile; Rahmouni, Souad

2015-02-17

A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators of platelet function. This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of phospholipase Cγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen- and C-type lectin-like receptor 2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. DUSP3 plays a selective and essential role in collagen- and C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug. © 2014 American Heart Association, Inc.

An infant and mother with severe B12 deficiency: vitamin B12 status assessment should be determined in pregnant women with anaemia.

PubMed

Sobczyńska-Malefora, A; Ramachandran, R; Cregeen, D; Green, E; Bennett, P; Harrington, D J; Lemonde, H A

2017-08-01

The vitamin B 12 status of infants depends on maternal B 12 status during pregnancy, and during lactation if breastfed. We present a 9-month-old girl who was admitted to the metabolic unit for assessment of developmental delay. She was exclusively breastfed and the introduction of solids at 5 months was unsuccessful. Investigations revealed pancytopenia, undetectable B 12 and highly elevated methylmalonic acid and homocysteine. Methylmalonic acid and homocysteine normalised following B 12 injections. Marked catch-up of developmental milestones was noted after treatment with B 12 . Investigations of parents showed normal B 12 in the father and combined B 12 and iron deficiency in the mother. Maternal B 12 deficiency, most likely masked by iron deficiency, led to severe B 12 deficiency in the infant. Exclusive breastfeeding and a subsequent failure to wean exacerbated the infant's B 12 deficiency leading to developmental delay. This case highlights the need for development of guidelines for better assessment of B 12 status during pregnancy.

Food contamination as a pathway for lead exposure in children during the 2010-2013 lead poisoning epidemic in Zamfara, Nigeria.

PubMed

Tirima, Simba; Bartrem, Casey; von Lindern, Ian; von Braun, Margrit; Lind, Douglas; Anka, Shehu Mohamed; Abdullahi, Aishat

2018-05-01

In 2010, an estimated 400 to 500 children died of acute lead poisoning associated with artisanal gold mining in Zamfara, Nigeria. Processing of gold ores containing up to 10% lead within residential compounds put residents, especially children, at the highest risk. Principal routes of exposure were incidental ingestion and inhalation of contaminated soil and dusts. Several Nigerian and international health organizations collaborated to reduce lead exposures through environmental remediation and medical treatment. The contribution of contaminated food to total lead exposure was assessed during the environmental health response. Objectives of this investigation were to assess the influence of cultural/dietary habits on lead exposure pathways and estimate the contribution of contaminated food to children's blood lead levels (BLLs). A survey of village dietary practices and staple food lead content was conducted to determine dietary composition, caloric intakes, and lead intake. Potential blood lead increments were estimated using bio-kinetic modeling techniques. Most dietary lead exposure was associated with contamination of staple cereal grains and legumes during post-harvest processing and preparation in contaminated homes. Average post-harvest and processed cereal grain lead levels were 0.32mg/kg and 0.85mg/kg dry weight, respectively. Age-specific food lead intake ranged from 7 to 78μg/day. Lead ingestion and absorption were likely aggravated by the dusty environment, fasting between meals, and nutritional deficiencies. Contamination of staple cereal grains by highly bioavailable pulverized ores could account for as much as 11%-34% of children's BLLs during the epidemic, and were a continuing source after residential soil remediation until stored grain inventories were exhausted. Copyright © 2017. Published by Elsevier B.V.

Reduced Synchronization Persistence in Neural Networks Derived from Atm-Deficient Mice

PubMed Central

Levine-Small, Noah; Yekutieli, Ziv; Aljadeff, Jonathan; Boccaletti, Stefano; Ben-Jacob, Eshel; Barzilai, Ari

2011-01-01

Many neurodegenerative diseases are characterized by malfunction of the DNA damage response. Therefore, it is important to understand the connection between system level neural network behavior and DNA. Neural networks drawn from genetically engineered animals, interfaced with micro-electrode arrays allowed us to unveil connections between networks’ system level activity properties and such genome instability. We discovered that Atm protein deficiency, which in humans leads to progressive motor impairment, leads to a reduced synchronization persistence compared to wild type synchronization, after chemically imposed DNA damage. Not only do these results suggest a role for DNA stability in neural network activity, they also establish an experimental paradigm for empirically determining the role a gene plays on the behavior of a neural network. PMID:21519382

Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study.

PubMed

Mullis, Primus E; Robinson, Iain C A F; Salemi, Souzan; Eblé, Andrée; Besson, Amélie; Vuissoz, Jean-Marc; Deladoey, Johnny; Simon, Dominique; Czernichow, Paul; Binder, Gerhard

2005-04-01

Four distinct familial types of isolated GH deficiency have been described so far, of which type II is the autosomal dominant inherited form. It is mainly caused by mutations within the first 6 bp of intervening sequence 3. However, other splice site and missense mutations have been reported. Based on in vitro experiments and transgenic animal data, there is strong evidence that there is a wide variability in phenotype in terms of the severity of GH deficiency. Therefore, we studied a total of 57 subjects belonging to 19 families suffering from different splice site as well as missense mutations within the GH-1 gene. The subjects presenting with a splice site mutation within the first 2 bp of intervening sequence 3 (5'IVS +1/+2 bp) leading to a skipping of exon 3 were found to be more likely to present in the follow-up with other pituitary hormone deficiencies. In addition, although the patients with missense mutations have previously been reported to be less affected, a number of patients presenting with the P89L missense GH form, showed some pituitary hormone impairment. The development of multiple hormonal deficiencies is not age dependent, and there is a clear variability in onset, severity, and progression, even within the same families. The message of clinical importance from these studies is that the pituitary endocrine status of all such patients should continue to be monitored closely over the years because further hormonal deficiencies may evolve with time.

Iron deficiency and new insights into therapy.

PubMed

Low, Michael Sy; Grigoriadis, George

2017-07-17

Iron deficiency and iron deficiency anaemia remain prevalent in Australia. The groups at highest risk are pre-menopausal women, socially disadvantaged people and those of Indigenous background. Diagnosing iron deficiency using a full blood examination and iron studies can be difficult and can be further complicated by concomitant inflammation. Results of iron studies should always be interpreted as an overall picture rather than focusing on individual parameters. In difficult clinical scenarios, soluble transferrin receptor assays can be useful. Management of iron deficiency involves identification and treatment of the cause of iron deficiency, as well as effective iron replacement. Clinicians should always take a detailed history and perform a comprehensive physical examination of a patient with iron deficiency. Patients should be monitored even if a likely cause of iron deficiency is identified. Patients who fail to respond to iron replacement or maintain iron status should be referred for further investigation, including endoscopy to exclude internal bleeding. Both enteral and parenteral iron are effective at replacing iron. For most adult patients, we recommend trialling daily oral iron (30-100 mg of elemental iron) as the first-line therapy. Safety and efficacy of intravenous iron infusions have improved with the availability of a newer formulation, ferric carboxymaltose. Patients who fail to respond to oral iron replacement can be safely managed with intravenous iron. Blood transfusion for iron deficiency anaemia should be reserved for life-threatening situations and should always be followed by appropriate iron replacement.

Identification of candidate genes involved in early iron deficiency chlorosis signaling in soybean (Glycine max) roots and leaves

USDA-ARS?s Scientific Manuscript database

Iron is an essential micronutrient for all living things, required in plants for photosynthesis, respiration and metabolism. A lack of bioavailable iron in soil leads to iron deficiency chlorosis (IDC), causing a reduction in photosynthesis and interveinal yellowing of leaves. Soybeans (Glycine ma...

[Strategies to control vitamin A deficiency].

PubMed

Traoré, L; Banou, A A; Sacko, D; Malvy, D; Schémann, J F

1998-01-01

Vitamin A deficiency is a major public health problem in the countries of the Sahel. It causes xerophthalmia and high rates of child mortality and it occurs mostly in underdeveloped regions. People of all ages may suffer from vitamin A deficiency but it is a particular problem in pre-school-age children. Each year, about 250,000 children throughout the world become blind due to vitamin A deficiency. Measles, pneumonia and diarrhea reduce the child's reserves of retinol and increase the dietary requirement for vitamin A. Improvement of social conditions is a radical approach to preventing vitamin A deficiency. Three strategies are currently in use: horticultural activities and health education; fortification of food products; distribution of high-dose vitamin A capsules.

The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.

PubMed

Sachs, Benjamin D; Rodriguiz, Ramona M; Siesser, William B; Kenan, Alexander; Royer, Elizabeth L; Jacobsen, Jacob P R; Wetsel, William C; Caron, Marc G

2013-10-01

Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3β signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition.

Partial androgen deficiency, depression and testosterone treatment in aging men.

PubMed

Amore, Mario; Scarlatti, Fabiano; Quarta, Antonio Lucio; Tagariello, Pietro

2009-02-01

This study provides a critical review of the literature on depressive symptoms of partial androgen deficiency (PADAM) and their treatment with Testosterone (T). PADAM in aging males is responsible for a variety of behavioral symptoms, such as weakness, decreased libido and erectile dysfunction, lower psychological vitality, depressive mood, anxiety, insomnia, difficulty in concentrating, and memory impairment. The psychological and behavioural aspects of PADAM may overlap with signs and symptoms of major depression. Evidence of the relationship between androgen deficiency and male depression comes from studies that have assessed depression in hypogonadal subjects, the association between low T level and male depressive illness, and the antidepressant action of androgen replacement. The etiology of depressive symptoms of PADAM is multifactorial, and results from the interaction of the biological and psychosocial changes that take place during the mid-life transition. Although data derived from androgen treatment trials and androgen replacement do not support T treatment or replacement as more efficacious than placebo for major depressive disorder (MDD), the clinical impression is that, in some sub-threshold depressive syndromes, T may lead to antidepressant benefits.

Iron Deficiency in Autism and Asperger Syndrome.

ERIC Educational Resources Information Center

Latif, A.; Heinz, P.; Cook, R.

2002-01-01

Retrospective analysis of the full blood count and, when available, serum ferritin measurements of 96 children (52 with autism and 44 with Asperger syndrome) found six autistic children had iron deficiency and 12 of the 23 autistic children with serum ferritin measures were iron deficient. Far fewer Asperger children were iron deficient. Results…

Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

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

Sekiya, Motohiro; Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp; Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655

2009-09-25

It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets,more » leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.« less

A deficiency of the homeotic complex of the beetle Tribolium

NASA Technical Reports Server (NTRS)

Stuart, J. J.; Brown, S. J.; Beeman, R. W.; Denell, R. E.; Spooner, B. S. (Principal Investigator)

1991-01-01

In Drosophila, the establishment of regional commitments along most of the anterior/posterior axis of the developing embryo depends on two clusters of homeotic genes: the Antennapedia complex (ANT-C) and the bithorax complex (BX-C). The red flour beetle has a single complex (HOM-C) representing the homologues of the ANT-C and BX-C in juxtaposition. Beetles trans-heterozygous for two particular HOM-C mutations spontaneously generate a large deficiency, presumably by an exchange within the common region of two overlapping inversions. Genetic and molecular results indicate that this deficiency spans at least the interval between the Deformed and abdominal-A homologues. In deficiency homozygous embryos, all gnathal, thoracic and abdominal segments develop antennal appendages, suggesting that a gene(s) has been deleted that acts to distinguish trunk from head. There is no evidence that beetles have a homologue of the segmentation gene fushi tarazu of similar genomic location and function. On the basis of the genetic tractability, convenient genome size and organization of Tribolium, and its relatively long phylogenetic divergence from Drosophila (>300 million years), we have integrated developmental genetic and molecular analyses of the HOM-C. We isolated about 70 mutations in the complex representing at least six complementation groups. The homeotic phenotypes of adults and lethal embryos lead us to believe that these beetle genes are homologous with the Drosophila genes indicated in Fig. 1 (see text).

A deficiency of the homeotic complex of the beetle Tribolium.

PubMed

Stuart, J J; Brown, S J; Beeman, R W; Denell, R E

1991-03-07

In Drosophila, the establishment of regional commitments along most of the anterior/posterior axis of the developing embryo depends on two clusters of homeotic genes: the Antennapedia complex (ANT-C) and the bithorax complex (BX-C). The red flour beetle has a single complex (HOM-C) representing the homologues of the ANT-C and BX-C in juxtaposition. Beetles trans-heterozygous for two particular HOM-C mutations spontaneously generate a large deficiency, presumably by an exchange within the common region of two overlapping inversions. Genetic and molecular results indicate that this deficiency spans at least the interval between the Deformed and abdominal-A homologues. In deficiency homozygous embryos, all gnathal, thoracic and abdominal segments develop antennal appendages, suggesting that a gene(s) has been deleted that acts to distinguish trunk from head. There is no evidence that beetles have a homologue of the segmentation gene fushi tarazu of similar genomic location and function. On the basis of the genetic tractability, convenient genome size and organization of Tribolium, and its relatively long phylogenetic divergence from Drosophila (>300 million years), we have integrated developmental genetic and molecular analyses of the HOM-C. We isolated about 70 mutations in the complex representing at least six complementation groups. The homeotic phenotypes of adults and lethal embryos lead us to believe that these beetle genes are homologous with the Drosophila genes indicated in Fig. 1 (see text).

ATM protein is deficient in over 40% of lung adenocarcinomas.

PubMed

Villaruz, Liza C; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F; Stabile, Laura P; Siegfried, Jill M; Conrads, Thomas P; Smith, Neil R; O'Connor, Mark J; Pierce, Andrew J; Bakkenist, Christopher J

2016-09-06

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

ATM protein is deficient in over 40% of lung adenocarcinomas

PubMed Central

Villaruz, Liza C.; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F.; Stabile, Laura P.; Siegfried, Jill M.; Conrads, Thomas P.; Smith, Neil R.; O'Connor, Mark J.; Pierce, Andrew J.; Bakkenist, Christopher J.

2016-01-01

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year. PMID:27259260

Genetics Home Reference: leukocyte adhesion deficiency type 1

MedlinePlus

... adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Leukocyte adhesion deficiency type 1 is a ...

Japanese family with congenital factor VII deficiency.

PubMed

Sakakibara, Kanae; Okayama, Yoshiki; Fukushima, Kenji; Kaji, Shunsaku; Muraoka, Michiko; Arao, Yujiro; Shimada, Akira

2015-10-01

Congenital factor VII (FVII) deficiency is a rare bleeding disorder with autosomal recessive inheritance. The present female patient was diagnosed with congenital FVII deficiency because of low hepaplastin test (HPT), although vitamin K was given. Heterozygous p.A191T mutation was detected in the peripheral blood, and the same mutation was also found in the mother and sister. To the best of our knowledge, this is the fourth reported case of p.A191T mutation of FVII in the literature and the first to be reported in Japan. FVII coagulation activity (FVII:C) in asymptomatic heterozygous carriers is mildly reduced. Therefore, some patients may not be accurately diagnosed with congenital FVII deficiency. In infants with low HPT without vitamin K deficiency, congenital FVII deficiency should be considered. © 2015 Japan Pediatric Society.

Deficiency of Gpr1 improves steroid hormone abnormality in hyperandrogenized mice.

PubMed

Yang, Ya-Li; Sun, Li-Feng; Yu, Yan; Xiao, Tian-Xia; Wang, Bao-Bei; Ren, Pei-Gen; Tang, Hui-Ru; Zhang, Jian V

2018-05-24

Polycystic ovary syndrome (PCOS) is a complex genetic disease with multifarious phenotypes. Many researches use dehydroepiandrosterone (DHEA) to induce PCOS in pubertal mouse models. The aim of this study was to investigate the role of GPR1 in dehydroepiandrosterone (DHEA)-induced hyperandrogenized mice. Prepubertal C57BL/6 mice (25 days of age) and Gpr1-deficient mice were each divided into two groups and injected daily with sesame oil with or without DHEA (6 mg/100 g) for 21 consecutive days. Hematoxylin and eosin (H&E) staining was performed to determine the characteristics of the DHEA-treated ovaries. Real-time PCR was used to examine steroid synthesis enzymes gene expression. Granulosa cell was cultured to explore the mechanism of DHEA-induced, GPR1-mediated estradiol secretion. DHEA treatment induced some aspects of PCOS in wild-type mice, such as increased body weight, elevated serum testosterone, increased number of small, cystic, atretic follicles, and absence of corpus luteum in ovaries. However, Gpr1 deficiency significantly attenuated the DHEA-induced weight gain and ovarian phenotype, improving steroidogenesis in ovaries and estradiol synthesis in cultured granulosa cells, partially through mTOR signaling. In conclusion, Gpr1 deficiency leads to the improvement of steroid synthesis in mice hyperandrogenized with DHEA, indicating that GPR1 may be a therapeutic target for DHEA-induced hyperandrogenism.

Behavioral impairments in animal models for zinc deficiency

PubMed Central

Hagmeyer, Simone; Haderspeck, Jasmin Carmen; Grabrucker, Andreas Martin

2015-01-01

Apart from teratogenic and pathological effects of zinc deficiency such as the occurrence of skin lesions, anorexia, growth retardation, depressed wound healing, altered immune function, impaired night vision, and alterations in taste and smell acuity, characteristic behavioral changes in animal models and human patients suffering from zinc deficiency have been observed. Given that it is estimated that about 17% of the worldwide population are at risk for zinc deficiency and that zinc deficiency is associated with a variety of brain disorders and disease states in humans, it is of major interest to investigate, how these behavioral changes will affect the individual and a putative course of a disease. Thus, here, we provide a state of the art overview about the behavioral phenotypes observed in various models of zinc deficiency, among them environmentally produced zinc deficient animals as well as animal models based on a genetic alteration of a particular zinc homeostasis gene. Finally, we compare the behavioral phenotypes to the human condition of mild to severe zinc deficiency and provide a model, how zinc deficiency that is associated with many neurodegenerative and neuropsychological disorders might modify the disease pathologies. PMID:25610379

Carbohydrate metabolism in erythrocytes of copper deficient rats.

PubMed

Brooks, S P J; Cockell, K A; Dawson, B A; Ratnayake, W M N; Lampi, B J; Belonje, B; Black, D B; Plouffe, L J

2003-11-01

Dietary copper deficiency is known to adversely affect the circulatory system of fructose-fed rats. Part of the problem may lie in the effect of copper deficiency on intermediary metabolism. To test this, weanling male Long-Evans rats were fed for 4 or 8 weeks on sucrose-based diets containing low or adequate copper content. Copper deficient rats had significantly lower plasma and tissue copper as well as lower plasma copper, zinc-superoxide dismutase activity. Copper deficient rats also had a significantly higher heart:body weight ratio when compared to pair-fed controls. Direct measurement of glycolysis and pentose phosphate pathway flux in erythrocytes using (13)C NMR showed no differences in carbon flux from glucose or fructose to pyruvate but a significantly higher flux through the lactate dehydrogenase locus in copper deficient rats (approximately 1.3 times, average of glucose and glucose + fructose measurements). Copper-deficient animals had significantly higher erythrocyte concentrations of glucose, fructose, glyceraldehyde 3-phosphate and NAD(+). Liver metabolite levels were also affected by copper deficiency being elevated in glycogen and fructose 1-phosphate content. The results show small changes in carbohydrate metabolism of copper deficient rats.

7 CFR 1434.21 - Loan deficiency payments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... REGULATIONS FOR HONEY § 1434.21 Loan deficiency payments. (a) Loan deficiency payments shall be available for 2008 through 2012 crop honey. (b) In order to be eligible to receive loan deficiency payment for a crop of honey, the producer must: (1) Comply with all of the program requirements to be eligible to obtain...

7 CFR 1434.21 - Loan deficiency payments.

Code of Federal Regulations, 2011 CFR

2011-01-01

... REGULATIONS FOR HONEY § 1434.21 Loan deficiency payments. (a) Loan deficiency payments shall be available for 2008 through 2012 crop honey. (b) In order to be eligible to receive loan deficiency payment for a crop of honey, the producer must: (1) Comply with all of the program requirements to be eligible to obtain...

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.

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.