Publications by authors named "Megan Russell"

19 Publications

  • Page 1 of 1

Congenital myasthenic syndrome caused by a frameshift insertion mutation in .

Neurol Genet 2020 Aug 30;6(4):e468. Epub 2020 Jun 30.

theNeurogenomics Division (S.S., J.K., K.R., N.B., C.B., A.L.S., M.R., R.R., M.D.B., A.M.C., M.J.H, V.N., S.R.), Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ; Fulgent Genetics (S.P.S.), Temple City, CA; Department of Neurology (P.B.S.), University of California Los Angeles; David Geffen School of Medicine (P.B.S.), Los Angeles; Department of Pathology and Laboratory Medicine (H.L., S.F.N.), University of California, Los Angeles; Department of Human Genetics (H.L., S.F.N.), David Geffen School of Medicine; Department of Neurology (I.S.), Columbia University, Center for Statistical Genetics, New York; Department of Translational Genomics (D.W.C.), University of Southern California, Los Angeles; Providence Sacred Heart Medical Center and Children's Hospital (S.P.Y.), Spokane, WA; Department of Pathology (S.A.M), University of Iowa, Carver College of Medicine; and Neuromuscular Clinic and Research Center (K.S.), Phoenix, AZ.

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.

Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.

Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.

Conclusions: These results expand on the spectrum of known loss-of-function mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.
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http://dx.doi.org/10.1212/NXG.0000000000000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357421PMC
August 2020

Neonatal epileptic encephalopathy caused by de novo GNAO1 mutation misdiagnosed as atypical Rett syndrome: Cautions in interpretation of genomic test results.

Semin Pediatr Neurol 2018 07 16;26:28-32. Epub 2017 Aug 16.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ; Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ; School of Life Sciences, Arizona State University, Tempe, AZ. Electronic address:

Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.
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http://dx.doi.org/10.1016/j.spen.2017.08.008DOI Listing
July 2018

The presence of F cells with a fetal phenotype in adults with hemoglobinopathies limits the utility of flow cytometry for quantitation of fetomaternal hemorrhage.

Cytometry B Clin Cytom 2018 07 16;94(4):695-698. Epub 2017 Nov 16.

Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

Background: Detection and quantitation of fetomaternal hemorrhage (FMH) can be difficult in patients with pre-existing elevations of HbF, such as those with hemoglobinopathies. The aim of this study was to evaluate the utility of dual-color flow cytometry with the Fetal Cell Count Kit (FCCK) in differentiating adult and fetal HbF in this population, as compared to flow cytometry (FC) using HbF alone.

Methods: Peripheral blood was obtained from normal adults and patients with hemoglobinopathies (β-thalassemia and sickle cell disease), including a small number of pregnant females. Cord blood was used to spike some samples with 5% fetal cells. Analysis by single color (HbF) and dual-color (HbF and carbonic anhydrase) FC was performed on these samples. Fetal cells were defined as those with high HbF fluorescence on single-color FC, and those that were HbF + CA- using the FCCK. The quantity of fetal cells detected by each technique was compared.

Results: Forty-six adult patients were included. In non-pregnant adults with hemoglobinopathies, a population of red cells with a fetal cell phenotype were detected by both techniques. The dual-color method reported lower quantities of these cells. In nineteen samples spiked with cord blood the FCCK consistently underestimated the quantity of fetal cells.

Conclusions: Patients with β-thalassemia and sickle cell disease have a population of HbF-containing cells which are phenotypically similar to fetal cells. Even with dual-color flow cytometry (FCCK), the detection and quantification of FMH by flow cytometry in this population remains difficult. © 2017 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21598DOI Listing
July 2018

A method to reduce ancestry related germline false positives in tumor only somatic variant calling.

BMC Med Genomics 2017 10 19;10(1):61. Epub 2017 Oct 19.

Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA.

Background: Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers. However, matched germline samples are frequently not available such as with archival tissues, which makes it difficult to distinguish somatic from germline variants. While population databases may be used to filter out known germline variants, recent studies have shown private germline variants result in an inflated false positive rate in unmatched tumor samples, and the number germline false positives in an individual may be related to ancestry.

Methods: First, we examined the relationship between the germline false positives and ancestry. Then we developed and implemented a tumor only caller (LumosVar) that leverages differences in allelic frequency between somatic and germline variants in impure tumors. We used simulated data to systematically examine how copy number alterations, tumor purity, and sequencing depth should affect the sensitivity of our caller. Finally, we evaluated the caller on real data.

Results: We find the germline false-positive rate is significantly higher for individuals of non-European Ancestry largely due to the limited diversity in public polymorphism databases and due to population-specific characteristics such as admixture or recent expansions. Our Bayesian tumor only caller (LumosVar) is able to greatly reduce false positives from private germline variants, and our sensitivity is similar to predictions based on simulated data.

Conclusions: Taken together, our results suggest that studies of individuals of non-European ancestry would most benefit from our approach. However, high sensitivity requires sufficiently impure tumors and adequate sequencing depth. Even in impure tumors, there are copy number alterations that result in germline and somatic variants having similar allele frequencies, limiting the sensitivity of the approach. We believe our approach could greatly improve the analysis of archival samples in a research setting where the normal is not available.
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http://dx.doi.org/10.1186/s12920-017-0296-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649057PMC
October 2017

Case Report: Novel mutations in are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability.

F1000Res 2017 24;6:553. Epub 2017 Apr 24.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband's mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in might cause a dominant susceptibility to epilepsy.
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http://dx.doi.org/10.12688/f1000research.10588.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473401PMC
April 2017

A de novo missense mutation in ZMYND11 is associated with global developmental delay, seizures, and hypotonia.

Cold Spring Harb Mol Case Stud 2016 Sep;2(5):a000851

Center for Rare Childhood Disorders and Neurogenomics Division Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.

Recently, mutations in the zinc finger MYND-type containing 11 (ZMYND11) gene were identified in patients with autism spectrum disorders, intellectual disability, aggression, and complex neuropsychiatric features, supporting that this gene is implicated in 10p15.3 microdeletion syndrome. We report a novel de novo variant in the ZMYND11 gene (p.Ser421Asn) in a patient with a complex neurodevelopmental phenotype. The patient is a 24-yr-old Caucasian/Filipino female with seizures, global developmental delay, sensorineural hearing loss, hypotonia, dysmorphic features, and other features including a happy disposition and ataxic gait similar to Angelman syndrome. In addition, this patient had uncommon features including eosinophilic esophagitis and multiple, severe allergies not described in similar ZMYND11 cases. This new case further supports the association of ZMYND11 with autistic-like phenotypes and suggests that ZMYND11 should be included in the list of potentially causative candidate genes in cases with complex neurodevelopmental phenotypes.
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http://dx.doi.org/10.1101/mcs.a000851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002929PMC
September 2016

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

Mol Genet Genomic Med 2015 Jul 8;3(4):283-301. Epub 2015 Apr 8.

Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.

Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.
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http://dx.doi.org/10.1002/mgg3.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521965PMC
July 2015

Integration of Downstream Signals of Insulin-like Growth Factor-1 Receptor by Endoplasmic Reticulum Stress for Estrogen-Induced Growth or Apoptosis in Breast Cancer Cells.

Mol Cancer Res 2015 Oct 26;13(10):1367-76. Epub 2015 Jun 26.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas.

Unlabelled: Estrogen (E2) exerts a dual function on E2-deprived breast cancer cells, with both initial proliferation and subsequent induction of stress responses to cause apoptosis. However, the mechanism by which E2 integrally regulates cell growth or apoptosis-associated pathways remains to be elucidated. Here, E2 deprivation results in many alterations in stress-responsive pathways. For instance, E2-deprived breast cancer cells had higher basal levels of stress-activated protein kinase, c-Jun N-terminal kinase (JNK), compared with wild-type MCF-7 cells. E2 treatment further constitutively activated JNK after 24 hours. However, inhibition of JNK (SP600125) was unable to abolish E2- induced apoptosis, whereas SP600125 alone arrested cells at the G2 phase of the cell cycle and increased apoptosis. Further examination showed that inhibition of JNK increased gene expression of TNFα and did not effectively attenuate expression of apoptosis-related genes induced by E2. A notable finding was that E2 regulated both JNK and Akt as the downstream signals of insulin-like growth factor-1 receptor (IGFIR)/PI3K, but with distinctive modulation patterns: JNK was constitutively activated, whereas Akt and Akt-associated proteins, such as PTEN and mTOR, were selectively degraded. Endoplasmic reticulum-associated degradation (ERAD) was involved in the selective protein degradation. These findings highlight a novel IGFIR/PI3K/JNK axis that plays a proliferative role during the prelude to E2-induced apoptosis and that the endoplasmic reticulum is a key regulatory site to decide cell fate after E2 treatment.

Implications: This study provides a new rationale for further exploration of E2-induced apoptosis to improve clinical benefit.
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http://dx.doi.org/10.1158/1541-7786.MCR-14-0494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763612PMC
October 2015

An integrated framework for reporting clinically relevant biomarkers from paired tumor/normal genomic and transcriptomic sequencing data in support of clinical trials in personalized medicine.

Pac Symp Biocomput 2015 :56-67

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

The ability to rapidly sequence the tumor and germline DNA of an individual holds the eventual promise of revolutionizing our ability to match targeted therapies to tumors harboring the associated genetic biomarkers. Analyzing high throughput genomic data consisting of millions of base pairs and discovering alterations in clinically actionable genes in a structured and real time manner is at the crux of personalized testing. This requires a computational architecture that can monitor and track a system within a regulated environment as terabytes of data are reduced to a small number of therapeutically relevant variants, delivered as a diagnostic laboratory developed test. These high complexity assays require data structures that enable real-time and retrospective ad-hoc analysis, with a capability of updating to keep up with the rapidly changing genomic and therapeutic options, all under a regulated environment that is relevant under both CMS and FDA depending on application. We describe a flexible computational framework that uses a paired tumor/normal sample allowing for complete analysis and reporting in approximately 24 hours, providing identification of single nucleotide changes, small insertions and deletions, chromosomal rearrangements, gene fusions and gene expression with positive predictive values over 90%. In this paper we present the challenges in integrating clinical, genomic and annotation databases to provide interpreted draft reports which we utilize within ongoing clinical research protocols. We demonstrate the need to retire from existing performance measurements of accuracy and specificity and measure metrics that are meaningful to a genomic diagnostic environment. This paper presents a three-tier infrastructure that is currently being used to analyze an individual genome and provide available therapeutic options via a clinical report. Our framework utilizes a non-relational variant-centric database that is scaleable to a large amount of data and addresses the challenges and limitations of a relational database system. Our system is continuously monitored via multiple trackers each catering differently to the diversity of users involved in this process. These trackers designed in analytics web-app framework provide status updates for an individual sample accurate to a few minutes. In this paper, we also present our outcome delivery process that is designed and delivered adhering to the standards defined by various regulation agencies involved in clinical genomic testing.
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April 2016

Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.

Nat Genet 2014 May 23;46(5):427-9. Epub 2014 Mar 23.

1] Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA. [2] [3].

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.
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http://dx.doi.org/10.1038/ng.2928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332808PMC
May 2014

The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

Haematologica 2014 Apr 10;99(4):647-55. Epub 2014 Jan 10.

The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.
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http://dx.doi.org/10.3324/haematol.2013.093971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971074PMC
April 2014

Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

Rare Dis 2014 3;2(1):e967148. Epub 2014 Nov 3.

Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.(1-4) Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.
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http://dx.doi.org/10.4161/2167549X.2014.967148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755243PMC
March 2016

Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA.

Bone 2013 Jul 26;55(1):166-78. Epub 2013 Feb 26.

St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.

Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer.
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http://dx.doi.org/10.1016/j.bone.2013.02.016DOI Listing
July 2013

Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment.

Haematologica 2013 May 14;98(5):686-90. Epub 2012 Dec 14.

St Vincent’s Institute of Medical Research and Department of Medicine at St. Vincent’s Hospital, University of Melbourne, Fitzroy,Victoria, Australia.

Erythropoiesis stimulating agents are widely used for the treatment of anemia. Recently, we reported erythroid expansion with impaired B lymphopoiesis and loss of trabecular bone in C57BL/6 mice following ten days of treatment with low-dose short acting recombinant human erythropoietin. We have assessed erythropoietin against longer-acting darbepoietin-alfa at a comparable erythroid stimulatory dosage regime. Darbepoietin-alfa and erythropoietin induced similar in vivo erythropoietic expansion. Both agents induced an expansion of the colony-forming unit-erythroid populations. However, unlike erythropoietin, darbepoietin-alfa did not impair bone marrow B lymphopoiesis. Strikingly the bone loss observed with erythropoietin was not apparent following darbepoietin-alfa treatment. This analysis demonstrates that whilst darbepoietin-alfa has similar in vivo erythropoietic potency to erythropoietin, it preserves the bone marrow microenvironment. Thus erythropoietin and darbepoietin-alfa manifest different action showing that erythropoiesis stimulating agents have differential non-erythroid effects dependent on their duration of action.
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http://dx.doi.org/10.3324/haematol.2012.078709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640110PMC
May 2013

Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment.

Blood 2011 May 18;117(21):5631-42. Epub 2011 Mar 18.

St Vincent's Institute of Medical Research & Department of Medicine at St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.

Erythropoietin (Epo) has been used in the treatment of anemia resulting from numerous etiologies, including renal disease and cancer. However, its effects are controversial and the expression pattern of the Epo receptor (Epo-R) is debated. Using in vivo lineage tracing, we document that within the hematopoietic and mesenchymal lineage, expression of Epo-R is essentially restricted to erythroid lineage cells. As expected, adult mice treated with a clinically relevant dose of Epo had expanded erythropoiesis because of amplification of committed erythroid precursors. Surprisingly, we also found that Epo induced a rapid 26% loss of the trabecular bone volume and impaired B-lymphopoiesis within the bone marrow microenvironment. Despite the loss of trabecular bone, hematopoietic stem cell populations were unaffected. Inhibition of the osteoclast activity with bisphosphonate therapy blocked the Epo-induced bone loss. Intriguingly, bisphosphonate treatment also reduced the magnitude of the erythroid response to Epo. These data demonstrate a previously unrecognized in vivo regulatory network coordinating erythropoiesis, B-lymphopoiesis, and skeletal homeostasis. Importantly, these findings may be relevant to the clinical application of Epo.
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http://dx.doi.org/10.1182/blood-2010-11-320564DOI Listing
May 2011

System dynamics in medical education: a tool for life.

Adv Health Sci Educ Theory Pract 2012 May 22;17(2):203-10. Epub 2010 Jul 22.

Biomedical Engineering Research Group, School of Electrical & Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.

A course in system dynamics has been included in the first year of our university's six-year medical curriculum. System Dynamics is a discipline that facilitates the modelling, simulation and analysis of a wide range of problems in terms of two fundamental concepts viz. rates and levels. Many topics encountered in the medical school curriculum, from biochemistry to sociology, can be understood in this way. The course was introduced following a curriculum review process in which it was concluded that knowledge of systems would serve to enhance problem-solving skills and clinical reasoning. The specific characteristics of system dynamics, the widespread use of digital computers, and the availability of suitable software made it possible to introduce the course at this level. The syllabus comprises a brief review of relevant mathematics followed by system dynamics topics taught in the context of examples, which are primarily but not exclusively medical. It is anticipated that this will introduce new thought processes to medical students, including holistic thinking and improved graphical visualisation skills.
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http://dx.doi.org/10.1007/s10459-010-9237-4DOI Listing
May 2012

Interaction of selective serotonin reuptake inhibitors with neuronal nicotinic acetylcholine receptors.

Biochemistry 2010 Jul;49(27):5734-42

Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, Arizona 85308, USA.

We compared the interaction of fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), with the human (h) alpha4beta2, alpha3beta4, and alpha7 nicotinic acetylcholine receptors (AChRs) in different conformational states, using Ca(2+) influx, radioligand binding, and molecular docking approaches. The results established that (1) fluoxetine was more potent than paroxetine in inhibiting agonist-activated Ca(2+) influx on halpha4beta2 and halpha7 AChRs, whereas the potency of both SSRIs was practically the same in the halpha3beta4 AChR. [corrected] (2) SSRIs bind to the [(3)H]imipramine locus with a [corrected] higher affinity when the AChRs are in the desensitized states compared to the resting states. (3) The different receptor specificity for fluoxetine determined by their inhibitory potencies or binding affinities suggests different modes of interaction when the AChR is in the closed or activated state. (4) Neutral and protonated fluoxetine interacts with a binding domain located in the middle of the AChR ion channel. In conclusion, SSRIs inhibit the most important neuronal AChRs with potencies and affinities that are clinically relevant by binding to a luminal site that is shared with tricyclic antidepressants.
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http://dx.doi.org/10.1021/bi100536tDOI Listing
July 2010

Evaluation of autofocus algorithms for tuberculosis microscopy.

Annu Int Conf IEEE Eng Med Biol Soc 2007 ;2007:3489-92

Department of Electrical Engineering, University of the Witwatersrand.

Direct sputum smear microscopy is the most cost-effective method of screening suspected cases of tuberculosis (TB) in high-prevalence countries. Automated microscopy of sputum smears to detect TB would enable rapid screening of large numbers of samples. We evaluate autofocus algorithms for TB microscopy as a step in the development of an automated microscope. Three different focus measures (namely the energy of the image Laplacian, the variance of the log-histogram and the first order Gaussian derivative) are tested on sequences of images of sputum smear slides with varying degrees of content density. A combination of search methods is applied in conjunction with the focus measure to find the position of optimal focus.
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http://dx.doi.org/10.1109/IEMBS.2007.4353082DOI Listing
March 2008

Cognitive dysfunction in advanced heart failure and prospective cardiac assist device patients.

Ann Thorac Surg 2006 May;81(5):1738-44

College of Medicine, Drexel University, Philadelphia, Pennsylvania 19102, USA.

Background: Extended periods of hypoperfusion in an advanced heart failure (HF) places patients at high risk for neurobehavioral compromise, which has not been studied systematically. It is also not clear how intravenous inotropic therapy and mechanical cardiac assist devices (MCAD) affect cognitive function.

Methods: This prospective cross-sectional cognitive preliminary study evaluated 252 potential heart transplant candidates assessing functions in memory, motor, and processing speed. Patients were divided into three HF groups based on severity of disease: group 1 outpatients (n = 113), group 2 in-patients requiring inotropic infusion (n = 83), and group 3 inpatients likely requiring MCAD support (n = 56). Aggregate z-scores for memory, motor, and processing speed and independent samples t tests assessed intergroup differences on 13 cognitive measures.

Results: A broad pattern of cognitive impairment was observed within the advanced HF group; fewer deficits were found in group 1 outpatients and more severe deficits in group 3 MCAD subjects. A difference in motor functions was observed as the earliest abnormality, with group 3 showing significant changes compared with group 1. The most dramatic changes were seen in domain mental processing speed along with specific verbal and visual memory functions, which were slower in group 3 compared with groups 1 and 2.

Conclusions: Cognitive deficits are common in advanced HF and worsen with increasing severity of HF. Appropriately designed and randomized studies will be needed to demonstrate if earlier MCAD implantation is warranted to arrest cognitive dysfunction and better postimplantation adaptation.
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http://dx.doi.org/10.1016/j.athoracsur.2005.12.010DOI Listing
May 2006