Publications by authors named "Carol West"

24 Publications

  • Page 1 of 1

Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults.

BMJ Open 2020 12 7;10(12):e040122. Epub 2020 Dec 7.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal yet treatable disease. Several advances in treatment of VTE have been made over the past decades, but definition and reporting of outcomes across those studies are inconsistent. Development of an international core outcome set for clinical studies of interventions for VTE addresses this lack of standardisation. The first step in the development of a core outcome set is to conduct a scoping review which aims to generate an inclusive list of unique outcomes that have been reported in previous studies.

Methods And Analysis: MEDLINE, Embase and the Cochrane Central Register of Controlled Trials will be searched with no language restriction for prospective studies reporting on interventions for treatment of VTE in patients who are adult and non-pregnant. Records will be sorted in reverse chronological order. Study screening and data extraction will be independently performed by two authors in blocks based on date of publication, starting with 2015 to 2020 and subsequent 1-year periods, until no new outcome measures are identified from the set of included studies. After homogenising spelling and combining outcomes with the same meaning, a list of unique outcomes will be determined. Those outcomes will be grouped into outcome domains. Qualitative analysis and descriptive statistics will be used to report results.

Ethics And Dissemination: Ethical approval is not required for this study. The results of this scoping review will be presented at scientific conferences, published in a peer-reviewed journal, and they will provide candidate outcome domains to be considered in subsequent steps in the development of a core outcome set for clinical studies of interventions for VTE. PROTOCOL REGISTRATION DETAILS: http://hdl.handle.net/10393/40459.
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http://dx.doi.org/10.1136/bmjopen-2020-040122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722803PMC
December 2020

Public Health Response to Zika Virus Exposure of Air Force Members Deployed to Caribbean Islands, 2016.

Mil Med 2020 09;185(9-10):e1453-e1460

USAF School of Aerospace Medicine, 2510 5th Street, Bldg. 840, WPAFB, OH 45433.

Introduction: The emergence of Zika virus disease (ZVD) in areas of military operations provided a new opportunity for force health protection. ZVD infection had an estimated 4:1 asymptomatic-to-symptomatic ratio and can cause neurologic sequelae.

Materials And Methods: We provide a brief report of a field investigation utilizing laboratory-based surveillance and survey instruments to characterize ZVD risk among personnel deployed to the Dominican Republic in support of Operation NEW HORIZONS (NH). Additionally, we describe a cluster of 3 ZVD cases among 8 aircrew on a short mission to St. Croix (U.S. Virgin Islands).

Results: Following Operation NH, 6 of a total 189 deployed cohort members tested positive for ZVD by immunoglobulin M and confirmatory plaque reduction neutralization test (3.2%). Reverse transcription polymerase chain reaction testing in urine or serum was positive in 4 of those 6 cases. All 6 cases reported at least one symptom, with 5 reporting subjective fever and arthralgia and 4 reporting rash. Cases were less likely to have air-conditioned living quarters (odds ratio = 0.1; 95% confidence interval 0.02-0.77; P < 0.03), but were otherwise similar to non-cases. Likewise, in St. Croix, 3/8 tested positive by immunoglobulin M and plaque reduction neutralization test for an attack rate of 38%. Similar to Operation NH, all three cases were symptomatic with subjective fever (67%), arthralgia (67%), and/or rash (100%).

Conclusions: This field investigation identified differing, mission location-dependent ZVD attack rates and a 0:9 asymptomatic-to-symptomatic case ratio. As this was unexpected based on a previous report of a 4:1 ratio, it emphasizes the need to be cautious before generalizing outbreak characteristics between populations while also offering additional practical experience for force health protection.
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http://dx.doi.org/10.1093/milmed/usaa188DOI Listing
September 2020

Breech delivery.

Authors:
Carol West

Midwives 2014 ;17(1):24

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August 2014

Temporal and spatial trends in freshwater fish tissue mercury concentrations associated with mercury emissions reductions.

Environ Sci Technol 2014 Feb 4;48(4):2193-202. Epub 2014 Feb 4.

Office of Research and Standards, Massachusetts Department of Environmental Protection, 1 Winter Street, Boston, Massachusetts 02108, United States.

Mercury (Hg) concentrations were monitored from 1999 to 2011 in largemouth bass (LMB) and yellow perch (YP) in 23 lakes in Massachusetts USA during a period of significant local and regional Hg emissions reductions. Average LMB tissue Hg concentration decreases of 44% were seen in 13 of 16 lakes in a regional Hg "hotspot" area. YP in all lakes sampled in this area decreased 43% after the major emissions reductions. Comparative decreases throughout the remainder of the state were 13% and 19% for LMB and YP respectively. Annual tissue mercury concentration rate decreases were 0.029 (LMB) and 0.016 mg Hg/kg/yr (YP) in the hotspot. In lakes around the rest of the state, LMB showed no trend and YP Hg decreased 0.0068 mg Hg/kg/yr. Mercury emissions from major point sources in the hotspot area decreased 98%, and 93% in the rest of the state from the early 1990s to 2008. The significant declines in fish Hg concentrations in many lakes occurred over the second half of a two decade decrease in Hg emissions primarily from municipal solid waste combustors and, secondarily, from other combustion point sources. In addition to the substantial Hg emissions reductions achieved in Massachusetts, further regional, national and global emissions reductions are needed for fish Hg levels to decrease below fish consumption advisory levels.
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http://dx.doi.org/10.1021/es404302mDOI Listing
February 2014

Basis of the Massachusetts reference dose and drinking water standard for perchlorate.

Environ Health Perspect 2010 Jan;118(1):42-8

Massachusetts Department of Environmental Protection, Office of Research and Standards, Boston, Massachusetts 02108, USA.

Objective: Perchlorate inhibits the uptake of iodide in the thyroid. Iodide is required to synthesize hormones critical to fetal and neonatal development. Many water supplies and foods are contaminated with perchlorate. Exposure standards are needed but controversial. Here we summarize the basis of the Massachusetts (MA) perchlorate reference dose (RfD) and drinking water standard (DWS), which are considerably lower and more health protective than related values derived by several other agencies. We also review information regarding perchlorate risk assessment and policy.

Data Sources: MA Department of Environmental Protection (DEP) scientists, with input from a science advisory committee, assessed a wide range of perchlorate risk and exposure information. Health outcomes associated with iodine insufficiency were considered, as were data on perchlorate in drinking water disinfectants.

Data Synthesis: We used a weight-of-the-evidence approach to evaluate perchlorate risks, paying particular attention to sensitive life stages. A health protective RfD (0.07 microg/kg/day) was derived using an uncertainty factor approach with perchlorate-induced iodide uptake inhibition as the point of departure. The MA DWS (2 microg/L) was based on risk management decisions weighing information on perchlorate health risks and its presence in certain disinfectant solutions used to treat drinking water for pathogens.

Conclusions: Current data indicate that perchlorate exposures attributable to drinking water in individuals at sensitive life stages should be minimized and support the MA DEP perchlorate RfD and DWS. Widespread exposure to perchlorate and other thyroid toxicants in drinking water and foods suggests that more comprehensive policies to reduce overall exposures and enhance iodine nutrition are needed.
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http://dx.doi.org/10.1289/ehp.0900635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831965PMC
January 2010

SLC40A1 c.1402G-->a results in aberrant splicing, ferroportin truncation after glycine 330, and an autosomal dominant hemochromatosis phenotype.

Acta Haematol 2007 21;118(4):237-41. Epub 2007 Dec 21.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif, USA.

Background/aims: To determine the molecular basis of a mild hemochromatosis phenotype in a man of Scottish-Irish descent.

Methods: We sequenced genomic DNA to detect mutations of HFE, SLC40A1, TFR2, HAMP, and HFE2. RNA isolated from blood mononuclear cells was used to make cDNA. RT-PCR was performed to amplify ferroportin from cDNA, and amplified products were visualized by electrophoresis and sequenced.

Results: The proband was heterozygous for the novel mutation c.1402G-->A (predicted G468S) in exon 7 of the ferroportin gene (SLC40A1). Located in the last nucleotide before the splice junction, this mutation results in aberrant splicing to a cryptic upstream splice site located at nt 990 within the same exon. This causes truncation of ferroportin after glycine 330 and the addition of 4 irrelevant amino acids before terminating. The truncated ferroportin protein, missing its C-terminal 241 amino acids, would lack all structural motifs beyond transmembrane region 7. The patient was also heterozygous for the common HFE H63D polymorphism, but did not have coding region mutations in TFR2, HAMP, or HFE2.

Conclusions: We conclude that this patient represents a unique example of hemochromatosis due to a single base-pair mutation of SLC40A1 that results in aberrant splicing and truncation of ferroportin.
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http://dx.doi.org/10.1159/000112830DOI Listing
February 2008

SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent.

Blood Cells Mol Dis 2007 Sep-Oct;39(2):206-11. Epub 2007 May 9.

Southern Iron Disorders Center, G105, 2022 Brookwood Medical Center Drive, Birmingham, AL 35209, USA.

The ferroportin polymorphism SLC40A1 Q248H (exon 6, cDNA 744G-->T; Gln248His) occurs in persons of sub-Saharan African descent with and without iron overload, and is associated with elevated serum ferritin concentrations (SF). However, the risk of iron overload associated with Q248H has not been defined. We tabulated previously reported Q248H allele frequency estimates in African-Americans and Native Africans, and computed the risk of iron overload associated with Q248H in subjects who lacked HFE C282Y. The aggregate Q248H allele frequency in 1038 African-Americans in two cohorts from Alabama and one cohort each from Washington, DC and California was 0.0525 (95% CI: 0.0451, 0.0652); there was no significant difference in frequencies across these cohorts. The aggregate frequency in 259 Natives from southeast Africa in two cohorts was 0.0946 (95% CI: 0.0694, 0.1198); the difference between the frequencies of these cohorts was not significant. The aggregate Q248H frequencies in African-Americans and Native Africans differed significantly (0.0525 vs. 0.0946, respectively; p=0.0021). There were reports of 24 unrelated African-Americans and 15 unrelated Native Africans without HFE C282Y who had iron overload. In African-Americans, the odds ratio (OR) of Q248H-associated risk of iron overload using 610 C282Y-negative control subjects unselected for SF was 1.57 (95% CI: 0.52, 4.72; p=0.29). In Native Africans, the OR using 208 control subjects unselected for SF was 1.05 (95% CI: 0.28, 3.90; p=0.58). We conclude that the frequency of SLC40A1 Q248H is significantly lower in African-Americans than in Native Africans. Although OR estimates of iron overload in African-Americans and Native Africans with Q248H were greater than unity, the increased OR were not statistically significant.
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http://dx.doi.org/10.1016/j.bcmd.2007.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986732PMC
September 2007

Iron overload and prolonged ingestion of iron supplements: clinical features and mutation analysis of hemochromatosis-associated genes in four cases.

Am J Hematol 2006 Oct;81(10):760-7

Southern Iron Disorders Center, Birmingham, Alabama, USA.

We evaluated and treated four white adults (one man, three women) who had iron overload associated with daily ingestion of iron supplements for 7, 15, 35, and 61 years, respectively. We performed HFE mutation analysis to detect C282Y, H63D, and S65C in each patient; in two patients, HFE exons were sequenced. In two patients, direct sequencing was performed to detect coding region mutations of TFR2, HAMP, FPN1, HJV, and ALAS2. Patients 1-4 ingested 153, 547, 1,341, and 4,898 g of inorganic iron as supplements. Patient 1 had hemochromatosis, HFE C282Y homozygosity, and beta-thalassemia minor. Patient 2 had spherocytosis and no HFE coding region mutations. Patient 3 had no anemia, a normal HFE genotype, and no coding region mutations in HAMP, FPN1, HJV, or ALAS2; she was heterozygous for the TFR2 coding region mutation V583I (nt 1,747 G-->A, exon 15). Patient 4 had no anemia and no coding region mutations in HFE, TFR2, HAMP, FPN1, HJV, or ALAS2. Iron removed by phlebotomy was 32.4, 10.4, 15.2, and 4.0 g, respectively. There was a positive correlation of log(10) serum ferritin and the quantity of iron removed by phlebotomy (P = 0.0371). Estimated absorption of iron from supplements in patients 1-4 was 20.9%, 1.9%, 1.1%, and 0.08%. We conclude that the clinical phenotypes and hemochromatosis genotypes of adults who develop iron overload after ingesting iron supplements over long periods are heterogeneous. Therapeutic phlebotomy is feasible and effective, and would prevent complications of iron overload.
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http://dx.doi.org/10.1002/ajh.20714DOI Listing
October 2006

Genetic polymorphisms and susceptibility to lung disease.

J Negat Results Biomed 2006 Apr 11;5. Epub 2006 Apr 11.

The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, 92037, USA.

Susceptibility to infection by bacterium such as Bacillus anthracis has a genetic basis in mice and may also have a genetic basis in humans. In the limited human cases of inhalation anthrax, studies suggest that not all individuals exposed to anthrax spores were infected, but rather, individuals with underlying lung disease, particularly asthma, sarcoidosis and tuberculosis, might be more susceptible. In this study, we determined if polymorphisms in genes important in innate immunity are associated with increased susceptibility to infectious and non-infectious lung diseases, particularly tuberculosis and sarcoidosis, respectively, and therefore might be a risk factor for inhalation anthrax. Examination of 45 non-synonymous polymorphisms in ten genes: p47phox (NCF1), p67phox (NCF2), p40phox (NCF4), p22phox (CYBA), gp91phox (CYBB), DUOX1, DUOX2, TLR2, TLR9 and alpha 1-antitrypsin (AAT) in a cohort of 95 lung disease individuals and 95 control individuals did not show an association of these polymorphisms with increased susceptibility to lung disease.
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http://dx.doi.org/10.1186/1477-5751-5-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475880PMC
April 2006

Birth story comments.

Authors:
Carol West

RCM Midwives 2005 Apr;8(4):174

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April 2005

Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume.

Blood 2005 Jul 24;106(2):740-5. Epub 2005 Mar 24.

The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA.

The average results of some laboratory measurements, including the hemoglobin, mean corpuscular volume (MCV), serum transferrin saturation (TS), serum ferritin, and white blood cell count of African-Americans differ from those of whites. Anonymized samples and laboratory data from 1491 African-American and 31 005 white subjects, approximately equally divided between men and women, were analyzed. The hematocrit, hemoglobin, MCV, TS, and white blood cell counts of African-Americans were lower than those of whites; serum ferritin levels were higher. When iron-deficient patients were eliminated from consideration the differences in hematocrit, hemoglobin, and MCV among women were slightly less. The -3.7-kilobase alpha-thalassemia deletion accounted for about one third of the difference in the hemoglobin levels of African-Americans and whites and neither sickle trait nor elevated creatinine levels had an effect. Among all subjects, 19.8% of African-American women would have been classified as "anemic" compared with 5.3% of whites. Among men, the figures were 17.7% and 7.6%. Without iron-deficient or thalassemic subjects, the difference had narrowed to 6.1% and 2.77% and to 4.29% and 3.6%, respectively. Physicians need to take into account that the same reference standards for hemoglobin, hematocrit, MCV, and TS and the white blood cell count do not apply to all ethnic groups.
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http://dx.doi.org/10.1182/blood-2005-02-0713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895180PMC
July 2005

Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features.

Blood Cells Mol Dis 2005 Mar-Apr;34(2):157-61

Hematology/Oncology Division, Rochester General Hospital, Mary M Gooley Hemophilia Center, 1425 Portland Avenue, Rochester, NY 14621, USA.

Hereditary hemochromatosis is a common disorder of iron metabolism most frequently associated with mutations in the HFE gene. Hereditary hemochromatosis may be caused by other less common genetic mutations including those in the ferroportin gene. Whereas hereditary hemochromatosis associated with HFE mutations is an autosomal recessive disorder, essentially all cases of hereditary hemochromatosis associated with ferroportin mutations follow an autosomal dominant pattern of inheritance, and most cases are notable for the lack of an elevated transferrin saturation and presence of iron deposition in Kupffer cells. This report describes the clinical and laboratory features of a family with hereditary hemochromatosis associated with a previously unrecognized ferroportin mutation (Cys326Ser). Three generations of the family are described. The disease in this family is notable for young age at onset, elevated transferrin saturation values, and hepatocyte iron deposition. The distinct molecular and clinical features reflect the heterogeneous nature of this disease.
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http://dx.doi.org/10.1016/j.bcmd.2004.12.002DOI Listing
September 2005

Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease.

J Lab Clin Med 2004 Aug;144(2):65-8

The Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037-1000, USA.

Patients with Gaucher disease have a deficiency of the lysosomal acid beta-glucosidase. The phenotypes of genotypically identical patients with Gaucher disease may differ markedly. We have examined the possibility that polymorphisms in another beta-glucosidase are responsible for this variability in the phenotype. Sequence analysis of the gene encoding cytosolic beta-glucosidase (GBA3) from 4 chromosomes revealed the presence of 4 single-nucleotide substitutions: c.316 G -->A (D106N), c.1353A-->G (Y451Y), c.1368T-->A (Y456X), and c.1540 to 1541AG -->T in the 3' untranslated region. We examined the DNA from 62 patients with Gaucher disease who were homozygous for the 1226A-->G (N370S) mutation and from 542 control subjects from various populations for these polymorphisms. Six of the possible 16 haplotypes were found, and none was over- or underrepresented among patients with the severe Gaucher disease phenotypes compared with those from patients with mild phenotypes.
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http://dx.doi.org/10.1016/j.lab.2004.03.013DOI Listing
August 2004

Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Am J Hematol 2004 Apr;75(4):205-8

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.

A 28-year-old asymptomatic male of Iranian Jewish (Meshadi) heritage was found on routine exam to have an erythrocytosis (RBC = 6.22 x 10(12)/l, Hgb = 19.2 g/dl, Hct = 58.9%). Splenomegaly was absent on physical exam. There was no family history of erythrocytosis. His oxygen dissociation curve was left-shifted with a p50 of 19 mmHg (normal = 25-32 mmHg). Hemoglobin electrophoresis showed no abnormalities. DNA sequencing of the hemoglobin beta globin gene and both alpha globin genes did not reveal a mutation. A 2,3-bisphosphoglycerate (BPG) level was markedly decreased at 0.3 micromol/g Hb (normal = 11.4-19.4 micromol/g Hb). The patient's bisphosphoglycerate mutase (BPGM) enzyme activity was also markedly decreased at 0.16 IU/g Hb (normal = 4.13-5.43 IU/g Hb). A red cell enzyme panel revealed a markedly decreased G-6-PD level (0.3 U/g Hb, normal = 8.6-18.6 U/g Hb). His parents and a brother were also available for evaluation. Both parents showed normal 2,3-BPG levels but BPGM activity approximately 50% of normal. Paradoxically, the brother showed normal BPGM activity but a slightly decreased 2,3-BPG level. All family members had markedly decreased G-6-PD activity. DNA sequencing of the BPGM gene showed the propositus to be homozygous for 185 G-->A, Arg 62 Gln in exon 2. Thus, the erythrocytosis in this patient is secondary to low 2,3-BPG levels, due to a deficiency in BPG mutase. This appears due to consanguinity within this family.
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http://dx.doi.org/10.1002/ajh.20014DOI Listing
April 2004

Genotypic and phenotypic heterogeneity of African Americans with primary iron overload.

Blood Cells Mol Dis 2003 Nov-Dec;31(3):310-9

Southern Iron Disorders Center, G-105, 20220 Brookwood Medical Center Drive, Birmingham, AL 35209, USA.

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
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http://dx.doi.org/10.1016/s1079-9796(03)00166-9DOI Listing
July 2004

Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans.

Blood Cells Mol Dis 2003 Nov-Dec;31(3):305-9

Department of Molecular and Experimental Medicine, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

We find that in the Black American population average ferritin levels are higher than those in Whites, both among men and women. African-Americans have an increased prevalence of iron storage disease characterized by prominent iron deposition in macrophages of the liver and other organs. The iron distribution in patients with mutations of the ferroportin gene is similar. A c.744 G-->T (Gln 248 His) mutation was detected among African-Americans at polymorphic frequencies. This variant is associated with increased ferritin levels in African-Americans and may play a role in their propensity to develop iron overload.
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http://dx.doi.org/10.1016/s1079-9796(03)00165-7DOI Listing
July 2004

Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia.

Blood 2003 Jul 20;102(1):353-6. Epub 2003 Mar 20.

Red Cell Patholology Unit, ICMHO-IDIBAPS, Hospital Clinic i Provincial, Villarroel 170, 08036-Barcelona, Spain.

We report here 2 patients with chronic nonspherocytic hemolytic anemia (CNSHA) and severe red blood cell (RBC) adenylate kinase (AK) deficiency. One of these patients, a boy of Spanish origin, exhibited a neonatal icterus and splenomegaly and required blood transfusions until the age of 2 years. The other patient was a white, American infant born to parents who were first cousins; he also presented with neonatal icterus and anemia. In neither case was psychomotor impairment observed. The first patient was found to be a compound heterozygote for 2 different missense mutations, 118G>A(Gly40Arg) and 190G>A(Gly64Arg) (cDNA sequence first described by Matsuura et al, 1989). The second patient was homozygous for an in-frame deletion (GAC) from nucleotide (nt) 498 to 500 or nt 501 to 503 of the cDNA sequence, predicting deletion of either aspartic acid (Asp) 140 or 141. The crystal structure of porcine cytosolic AK was used as a molecular model to investigate how these mutations may affect enzyme structure and function.
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http://dx.doi.org/10.1182/blood-2002-07-2288DOI Listing
July 2003

Seeking candidate mutations that affect iron homeostasis.

Blood Cells Mol Dis 2002 Nov-Dec;29(3):471-87

Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM215, 10550 North Torrey Pines Road, La Jolla, CA 92014, USA.

Hereditary hemochromatosis is characterized by marked variation of expression of the defect: very few homozygotes with the C282Y/C282Y HFE genotype have full-blown clinical disease, a larger number show biochemical stigmata of iron overload, and some seem normal biochemically. The following candidate genes have been examined in detail to determine whether polymorphisms in them may be responsible for this variation: transferrin, transferrin receptor 1, transferrin receptor 2, ferritin-L, ferritin-H, IRP1, IRP2, HFE, beta(2) microglobulin, mobilferrin/calreticulin, ceruloplasmin, ferroportin, NRAMP1, NRAMP2 (DMT1), haptoglobin, heme oxygenase-1, heme oxygenase-2, hepcidin, USF2, ZIRTL, duodenal cytochrome b ferric reductase (DCYTB), TNFalpha, keratin 8, and keratin 18. The coding sequence, exon-intron junctions, and promoters of each of these genes was sequenced in DNA from 20 subjects: 5 HFE C282Y/C282Y with clinical disease, 5 HFE C282Y/C282Y with normal/low ferritin levels and no disease, 5 wt/wt with high ferritin and transferrin saturation, and 5 wt/wt normal controls. When coding or promoter polymorphisms were encountered, DNA from large numbers of ethnically defined subjects was examined for these polymorphisms and a relationship between their existence and abnormalities of iron homeostasis was sought. Only in the case of one transferrin mutation did we find a strong relationship between the polymorphism and iron deficiency anemia. The putative genes that affect the expression of HFE mutations remain elusive.
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http://dx.doi.org/10.1006/bcmd.2002.0586DOI Listing
November 2003

Polymorphisms in glucosylceramide (glucocerebroside) synthase and the Gaucher disease phenotype.

Isr Med Assoc J 2002 Nov;4(11):986-8

Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA, USA.

Background: Gaucher disease results from the accumulation of glucosylceramide (glucocerebroside) in tissues of affected persons. Patients sharing the same genotype present with widely varying degrees of lipid storage and of clinical manifestations.

Objectives: To determine whether variation in the glucosylceramide synthase (UDPGlucose ceramide glucosyltransferase) gene, which encodes the enzyme that regulates the synthesis of glucocerebroside, could account for the variability and clinical manifestations.

Methods: Patients homozygous for the 1226G (N370S) mutation, the most common in the Ashkenazi Jewish population, were investigated. The exons and flanking sequences of the gene were sequenced using DNA derived from five very mild Gaucher disease patients and four patients with relatively severe Gaucher disease.

Results: One polymorphism was found in the coding region, but this did not change any amino acids. Seven other polymorphisms were found in introns and in the 5' untranslated region. Some of these were single nucleotide polymorphisms; others were insertions. The mutations appear to be in linkage equilibrium and none were found with a significantly higher frequency in either severe or mildly affected individuals.

Conclusions: Mutations in the glucosylceramide synthase gene do not appear to account for the variability in expression of the common Jewish Gaucher disease mutation.
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November 2002

Polymorphisms in iron-responsive binding protein 2 and lack of association with sporadic Parkinson's disease.

Mov Disord 2002 Nov;17(6):1302-4

The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California 92037, USA.

Mice with targeted disruptions in the iron-responsive binding protein 2 (IRP2) gene accumulate iron in distinct regions of the brain and develop neurodegenerative characteristics resembling Parkinson's disease after 6 months of age. To determine whether polymorphisms in IRP2 predispose humans to Parkinson's disease (PD), we sequenced the IRP2 gene of subjects with sporadic PD and normal controls. Three polymorphisms which result in an amino acid change were identified: L159V, F272L, and T560I. The L159V and T560I polymorphisms, identified in an African-American PD subject, were found in the African-American population at an allele frequency of 0.102 (n = 1,236) and 0.111 (n = 1,228), respectively, and were not associated with an increased prevalence of PD. The F272L polymorphism was found in a normal 58-year-old, Caucasian subject whose father had PD, but it was not observed in 38 additional patients with sporadic PD. The F272L polymorphism occurred at an allele frequency of 0.0014 (n = 1,384) in the normal Caucasian population. Additional F272L heterozygous subjects identified in the normal population did not have a family or personal history of PD. We conclude that these IRP2 polymorphisms do not play an important role in the development of sporadic cases of PD. It remains to be determined whether other polymorphisms in IRP2 play a role in familial PD.
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http://dx.doi.org/10.1002/mds.10253DOI Listing
November 2002

Polymorphisms in the 5' flanking region of the HFE gene: linkage disequilibrium and relationship to iron homeostasis.

Blood Cells Mol Dis 2002 Mar-Apr;28(2):191-5

Department of Molecular and Experimental Medicine, Division of Hematology, The Scripps Research Institute, La Jolla, California 92037, USA.

We have discovered two single-nucleotide polymorphisms in the 5' flanking region of the HFE gene. These mutations are -970 T-->G and -467 C-->G, numbering from the ATG start codon. When a T was present at -970, a C was always found at -467. The C allele was the less common at nt -467 with a gene frequency of 0.31 in white subjects with wild-type HFE. Slightly lower gene frequencies were observed in a small number of Hispanic and African-American subjects and a slightly higher frequency in a few Asian subjects. The less common -467 mutation was found in almost 12 chromosomes that bore the 845G-->A (C282Y) mutation and was significantly more prevalent in chromosomes containing the 187C-->G (H63D) mutation. Although this mutation is near an HNF3B/HFH2 site, its presence did not seem to affect iron metabolism as judged by the serum ferritin or transferrin saturation levels. The tighter association of the -467 polymorphism with the C282Y mutation is consistent with other data that suggest that the C282Y mutation has occurred relatively recently and that the H63D mutation is considerably older.
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http://dx.doi.org/10.1006/bcmd.2002.0509DOI Listing
August 2003

Erythrocyte viability in blood salvaged during total joint arthroplasty with cement.

J Bone Joint Surg Am 2002 Jan;84(1):23-5

Scripps Clinic, La Jolla, CA 92037, USA.

Background: Erythrocyte salvage, the collection of a patient's blood shed from the surgical wound, is one aspect of blood management. Previous investigators have examined salvaged blood for content; however, to our knowledge, none have examined the viability of erythrocytes after exposure to the chemical and thermal reactions produced by motorized instruments and polymethylmethacrylate during surgery. The purpose of this study was to determine the viability of salvaged erythrocytes from patients undergoing primary total joint arthroplasty with cement.

Methods: Erythrocyte viability studies were performed on specimens from three subjects with use of a double isotope-labeling technique employing chromium-51 and technetium-99m. With use of a fresh blood specimen obtained prior to surgery and a specimen of salvaged blood that had been recycled, washed, and filtered with use of the Cell Saver, the viability of the Cell-Saver-processed erythrocytes, labeled with chromium-51, was calculated on the basis of the technetium-99m-labeled red blood-cell mass.

Results: The mean erythrocyte viability (and standard deviation) in blood salvaged with use of the Cell Saver was 88.0% +/- 3.8%. The standard of the American Association of Blood Banks for minimum erythrocyte viability in adequately cross-matched allogeneic blood or predeposited autologous blood is 70%.

Conclusions: The high rate of viability of the erythrocytes in this study shows that the Cell Saver is a valuable adjunct to other blood management techniques for patients having total joint arthroplasty. We believe that the very high mean rate of erythrocyte viability and the extremely small standard deviation in our three subjects, as compared with the standards of the American Association of Blood Banks, made additional study subjects unnecessary.
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http://dx.doi.org/10.2106/00004623-200201000-00004DOI Listing
January 2002

Commentary.

Blood Cells Mol Dis 1996 Apr;22(1):47

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http://dx.doi.org/10.1006/bcmd.1996.0007DOI Listing
April 1996