PubMed Health⌕ Search

Biomedical subjects

M J Ackerman

Publications and source records attributed to M J Ackerman.

At least 19 recordsLinked to original sources
PubMed2004

Beta-blocker therapy failures in symptomatic probands with genotyped long-QT syndrome.

Beta-blocker therapy is one of the principal therapies for congenital long-QT syndrome (LQTS). However, breakthrough cardiac events occur while being treated with beta-blockers. We sought to determine the frequency of and clinical correlates underlying beta-blocker therapy failures in genotyped, symptomatic LQTS probands. The medical records were analyzed only for genotyped LQTS probands who presented with a LQTS-attributable clinical event and were receiving beta-blocker therapy. The study cohort comprised 28 such patients: 18 KCNQ1/KVLQT1(LQT1), 7 KCNH2/HERG (LQT2), and 3 SCN5A (LQT3). The prescribed beta-blocker was atenolol (12), propranolol (10), metoprolol (4), and nadolol (2). Beta-blocker therapy failure was defined as breakthrough cardiac events including syncope, aborted cardiac arrest (ACA), appropriate implantable cardioverter-defibrillator (ICD) therapy, or sudden death occurring while on beta-blocker therapy. During a median follow-up of 46 months, 7/28 (25%) LQTS probands experienced a total of 15 breakthrough cardiac events. Their initial presentation was ACA (3), bradycardia during infancy (2), and syncope (2). The underlying genotype was KVLQT1 (6) and HERG (1). Two breakthroughs were attributed to noncompliance. Of the 13 breakthroughs occurring while compliant, 10 occurred with atenolol and 3 with propranolol (p = 0.03). In this study cohort, one-fourth of genotyped LQTS probands failed beta-blocker therapy. Treatment with atenolol, young age at diagnosis, initial presentation with ACA, KVLQT1 genotype, and noncompliance may be important factors underlying beta-blocker therapy failures.

Adrenergic beta-Antagonists↗
PubMed2002

SCN5A is expressed in human jejunal circular smooth muscle cells.

Tetrodotoxin-resistant Na+currents are expressed in a variety of muscle cells including human jejunal circular smooth muscle (HJCSM) cells. The aim of this study was to determine the molecular identity of the pore-forming alpha-subunit of the HJCSM Na+ channel. Degenerate primers identified a cDNA fragment of 1.5 kb with 99% nucleotide homology with human cardiac SCN5A. The identified clone was also amplified from single smooth muscle cells by reverse transcriptase-polymerase chain reaction (RT-PCR). Northern blot analysis showed expression of full-length SCN5A. Laser capture microdissection was used to obtain highly purified populations of HJCSM cells. RT-PCR on the harvested cells showed that SCN5A was present in circular but not in longitudinal muscle. A similar result was obtained using a pan-Na+ channel antibody. The full-length sequence for SCN5A was obtained by combining standard polymerase chain reaction with 5' and 3' rapid amplification of cDNA end techniques. The intestinal SCN5A was nearly identical to the cardiac SCN5A. The data indicate that SCN5A is more widely distributed than previously thought and encodes the pore-forming alpha-subunit of the tetrodotoxin-resistant Na+ current in HJCSM cells.

Gene Expression Regulation↗
PubMed2001

Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.

CONTEXT: Fatal arrhythmias from occult long QT syndrome may be responsible for some cases of sudden infant death syndrome (SIDS). Because patients who have long QT syndrome with sodium channel gene (SCN5A) defects have an increased frequency of cardiac events during sleep, and a recent case is reported of a sporadic SCN5A mutation in an infant with near SIDS, SCN5A has emerged as the leading candidate ion channel gene for SIDS. OBJECTIVE: To determine the prevalence and functional properties of SCN5A mutations in SIDS. DESIGN, SETTING, AND SUBJECTS: Postmortem molecular analysis of 93 cases of SIDS or undetermined infant death identified by the Medical Examiner's Office of the Arkansas State Crime Laboratory between September 1997 and August 1999. Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses. Missense mutations were incorporated into the human heart sodium channel alpha subunit by mutagenesis, transiently transfected into human embryonic kidney cells, and characterized electrophysiologically. MAIN OUTCOME MEASURES: Molecular and functional characterization of SCN5A defects. RESULTS: Two of the 93 cases of SIDS possessed SCN5A mutations: a 6-week-old white male with an A997S missense mutation in exon 17 and a 1-month old white male with an R1826H mutation in exon 28. These 2 distinct mutations occurred in highly conserved regions of the sodium channel and were absent in 400 control patients (800 alleles). Functionally, the A997S and R1826H mutant channels expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. CONCLUSION: Approximately 2% of this prospective, population-based cohort of SIDS cases had an identifiable SCN5A channel defect, suggesting that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS.

Autopsy↗
PubMed2001

Pulmonary atresia with ventricular septal defect and persistent airway hyperresponsiveness.

OBJECTIVE: We and others have observed significant hyperinflation and airflow obstruction after the surgical repair of pulmonary atresia and ventricular septal defect. This study sought to objectively characterize this problem and determine the prevalence of airway hyperresponsiveness in these patients. METHODS: We performed a prospective study of children and young adults with pulmonary atresia and ventricular septal defect between June 1996 and December 1998. The participants were stratified into 2 distinct molecular genotypes on the basis of chromosome 22q11.2 microdeletion. A clinical diagnosis of asthma and an objective assessment of airway hyperresponsiveness were determined by means of an asthma inventory scale and methacholine challenge testing, respectively. Thirty-three patients were enrolled. Thirteen had velocardiofacial syndrome, each with chromosome 22q11.2 microdeletion. RESULTS: None of the nonsyndromic patients had evidence for haploinsufficiency. Overall, 66.7% (22/33) met criteria for a clinical diagnosis of airway hyperresponsiveness: 62% (8/13) from the microdeletion genotype and 70% (14/20) from the nonsyndromic group. CONCLUSIONS: We have identified an extremely strong association between pulmonary atresia and ventricular septal defect and persistent airway hyperresponsiveness. Haploinsufficiency at chromosome 22q11.2 did not contribute to this predilection for airway hyperresponsiveness. These results provide a basis to anticipate persistent respiratory difficulties after operations in patients with pulmonary atresia and ventricular septal defect. Moreover, this at-risk patient population may yield unique insights into fundamental mechanisms involved in the pathogenesis of airway hyperresponsiveness.

Adolescent↗
PubMed2001

Molecular autopsy of sudden unexplained death in the young.

Sudden unexplained death (SUD) claims over 4,000 persons between the age of 1 and 22 each year in the United States. Nearly half of all pediatric SUD cases have a normal structural autopsy evaluation and are dismissed without a diagnosis. With the discovery of the genetic basis for potentially fatal arrhythmias associated with the inherited long QT syndrome (LQTS), postmortem molecular diagnosis of this disorder is possible. The authors describe the results of a molecular autopsy performed on a 17-year-old boy found dead in bed. A novel clinical test involving an epinephrine challenge in the decedent's mother implicated a potential defect in the phase 3 potassium current encoded by the gene KVLQT1. Exon-specific amplification by polymerase chain reaction and direct DNA sequencing of KVLQT1 revealed a 5-base pair deletion in the genetic material recovered from the decedent's paraffin-embedded heart tissue. The ability to perform molecular autopsies on archived necropsy material undoubtedly will transform the forensic evaluation of SUD. The combination of catecholamine provocation testing in survivors and a postmortem LQTS gene analysis may unmask families with "concealed" LQTS and establish the cause and manner of death in SUDS.

Adolescent↗
PubMed2001

Diagnostic accuracy of screening electrocardiograms in long QT syndrome I.

OBJECTIVE: Inherited long QT syndrome (LQTS) may present with syncope, seizures, and/or sudden death as a result of ventricular tachyarrhythmias. Identification of family members who are at risk because they harbor the genetic substrate for LQTS is critical. Presently, such identification relies on the 12-lead electrocardiogram (ECG). The purpose of this study was to evaluate the efficacy of the automated ECG as a screening tool for LQTS. METHOD: Molecular testing of a proband and 22 additional family members for the KVLQT1 mutation and symptomatic status facilitated the classification of each family member into the following patient groups: noncarriers (13), asymptomatic carriers (5), and symptomatic carriers (5). Each individual had a standard 12-lead ECG from which the computer and manual (lead II) corrected QT interval were determined. In addition, we determined the accuracy of the computer ECG diagnostic interpretation for each patient group. RESULTS: With the use of a corrected QT interval of >/=460 ms as a diagnostic cutoff, the positive and negative predictive values for identifying at-risk individuals were 100%. Despite this, the computer-generated ECG diagnostic interpretation erroneously classified 6 of 23 family members. Moreover, half of the family members, proved to have the ion channel defect, received the diagnostic interpretation "normal ECG." CONCLUSION: Reliance on the computer-generated ECG diagnostic interpretation alone will fail to identify many at-risk family members. It is suggested that all first-degree relatives of an identified LQTS proband have a 12-lead ECG that is reviewed independently by a physician who is familiar with LQTS in an effort to improve screening for this potentially lethal syndrome.electrocardiogram, long QT syndrome, QT interval, sudden death.

Adult↗
PubMed2001

Anatomic modeling from unstructured samples using variational implicit surfaces.

We describe the use of variational implicit surfaces (level sets of an embedded generating function modeled using radial basis interpolants) in anatomic modeling. This technique allows the practitioner to employ sparsely and unevenly sampled data to represent complex biological surfaces, including data acquired as a series of non-parallel image slices. The method inherently accommodates interpolation across irregular spans. In addition, shapes with arbitrary topology are easily represented without interpolation or aliasing errors arising from discrete sampling. To demonstrate the medical use of variational implicit surfaces, we present the reconstruction of the inner surfaces of blood vessels from a series of endovascular ultrasound images.

Animals↗
PubMed2001

From data to knowledge--the Visible Human Project continues.

The U. S. National Library of Medicine (NLM) has long been a world leader in the archiving and distribution of the print-based images of biology and medicine. NLM has also been a pioneer in the use of computer systems to encode and distribute textual knowledge of the life sciences. NLM's Long Range Planning effort of 1985-86 foresaw a coming era where NLM's Bibliographic and factual database services would be complemented by libraries of digital images, distributed over high speed computer networks. The NLM Planning Panel on Electronic Imaging recommended that NLM should undertake the building a digital image library consisting of computerized tomography (CT) and magnetic resonance (MR) images, and cryosection images of a representative, carefully selected and prepared male and female cadaver--the "Visible Human Project ." The male and female Visible Human data sets are now being made available through a license agreement with the NLM. The data sets are supporting a wide range of educational, diagnostic, treatment planning, and commercial uses. The NLM, in partnership with other U.S. government research agencies has begun a three prong effort within the Visible Human Project to address: the creation of a new online, interactive, digital head-and-neck atlas; the development of a tool kit of computational programs capable of automatically performing many of the basic data handling functions required for using Visible Human data in applications; and the improved resolution of future Visible Human data sets through the reduction of the anatomical artifacts introduced by the methods used to stabilize and section the anatomical materials and the development of staining and wide-spectrum methods for increasing tissue contrast.

Anatomy, Artistic↗
PubMed2000

Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy.

Mutations in genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). The sarcomeric protein actin plays a central, dual role in cardiac myocytes, generating contractile force by interacting with myosin and also transmitting force within and between cells. Two missense mutations in the cardiac actin gene (ACTC), postulated to impair force transmission, have been associated with familial dilated cardiomyopathy (DCM). Recently, a missense mutation in ACTC was found to cosegregate with familial HCM. To further test the hypothesis that mutations within functionally distinct domains of ACTC cause either DCM or HCM, we performed mutational analyses in 368 unrelated patients with familial or sporadic HCM. Single strand conformation polymorphism and sequence analyses of genomic DNA were performed. De novo mutations in ACTC were identified in two patients with sporadic HCM who presented with syncope in early childhood. Patients were heterozygous for missense mutations resulting in Pro164Ala and Ala331Pro amino acid substitutions, adjacent to regions of actin-actin and actin-myosin interaction, respectively. A mutation that cosegregated with familial HCM was also found, causing a Glu99Lys substitution in a weak actomyosin binding domain. The cardiac phenotype in many affected patients was characterized by an apical form of HCM. These findings support the hypothesis that a single amino acid substitution in actin causes either congestive heart failure or maladaptive cardiac hypertrophy, depending on its effect on actin structure and function.

Actins↗
PubMed2000

A new research program in medical image data processing.

The National Library of Medicine, in partnership with the National Institute for Dental and Craniofacial Research, the National Eye Institute, the National Science Foundation, the National Institute for Deafness and Other Communication Disorders, and the National Cancer Institute, has founded a software consortium to support the creation of a public resource in high-dimension data processing tools. The initial emphasis of this effort is to provide public software tools in 3D segmentation and deformable and rigid registration, capable of analyzing the head-and-neck anatomy of the Visible Human Project data. The eventual goal is for the consortium to provide the cornerstone of a self-sustaining software community in 3D, 4D and higher dimensional data analysis. The consortium is committed to open-source code, public software including open interfaces supporting connections to a broad range of visualization and graphic user interface platforms.

Anatomy, Cross-Sectional↗
PubMed1999

The Visible Human Project: a resource for education.

Throughout recorded history, the relationships between biological structure and function have been central to the understanding of health and disease. For many centuries, the anatomy illustrations originally created during the medieval period formed the basis for the study of medicine. But learning and understanding anatomic structures is limited by the fundamentally two-dimensional images traditionally used to teach them. The digital computer now allows scientists to acquire, store, manipulate, and display complex images. In 1989, the National Library of Medicine (NLM) began a project to use computer technologies to build a prototype digital image library of data representing a complete normal adult human male and female. In this paper, the author describes the beginnings of this project, the Visible Human Project (VHP), the digital images currently available in the VHP database, ongoing research and development, and plans for the future of the VHP.

Adult↗
PubMed1999

Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome.

OBJECTIVE: To determine the genetic basis for long QT syndrome (LQTS) in a cohort of patients with a personal history or an extended family history of a swimming-triggered cardiac event. PATIENTS AND METHODS: After review of the Mayo Clinic unit medical record system, blood samples or archived autopsy tissue samples were obtained from a retrospective cohort of 35 cases diagnosed as having autosomal dominant LQTS. Exon-specific amplification by polymerase chain reaction and direct sequence analyses were performed on the entire KVLQT1 gene. RESULTS: Six cases had a personal history or an extended family history of a near drowning or drowning. In all 6 cases, LQTS-causing mutations in KVLQT1 gene were identified: 3 deletion mutations, 2 donor splice site mutations, and 1 missense mutation. One of the mutations, a novel donor splicing defect, was determined by postmortem molecular analysis of a paraffin-embedded tissue block from a 12-year-old girl who died in 1976. Distinct KVLQT1 mutations were demonstrated in 3 of the remaining 29 cases. The overall frequency of KVLQT1 defects in LQTS was 100% (6/6) in those with and 10% (3/29) in those without a personal history or an extended family history of drowning or near drowning (P<.001). CONCLUSION: Swimming appears to be a gene-specific (KVLQT1) arrhythmogenic trigger for LQTS. This study provides proof of principle that an unexplained drowning or near drowning may have a genetic basis.

Adolescent↗
PubMed1998

A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.

After identifying a 10-year-old boy with inherited long QT syndrome (LQTS) after a near-drowning that required defibrillation from torsades de pointes, evaluation of first degree relatives revealed a four-generation kindred comprising 26 individuals with four additional symptomatic and eight asymptomatic members harboring an abnormally prolonged QTc (defined as > or =0.46 s1/2). We set out to determine the molecular basis of their LQTS. The inherited LQTS represents a collection of genetically distinct ion channelopathies with over 40 mutations in four fundamental cardiac ion channels identified. Molecular studies, including linkage analysis and identification of the disease-associated mutation, were performed on genomic DNA isolated from peripheral blood samples from 29 available family members. Genetic linkage analysis excluded the regions for LQT2, LQT3, and LQT5. However, the chromosome 11p15.5 region (LQT1) showed evidence of linkage with a maximum lod score of 3.36. Examination of the KVLQT1 gene revealed a novel 3-bp deletion resulting in an in-frame deltaF339 (phenylalanine) deletion in the proband. This deltaF339 mutation was confirmed in nine additional family members who shared both an assigned affected phenotype and the disease-associated linked haplotype. Importantly, three asymptomatic family members, with a tentative clinical diagnosis based on their QTc, did not have this mutation and could be reclassified as unaffected. It is noteworthy that the proband's ECG suggested the sodium channel-based LQT3 genotype. These findings show the potential importance of establishing a molecular diagnosis rather than initiating genotype-specific interventions based upon inspection of a patient's ECG.

Chromosomes, Human, Pair 11↗
PubMed1998

The long QT syndrome.

The LQTS is no longer the rare "zebra" whose purpose is to ensure that trainees recall that deafness and sudden cardiac death may be related (Jervell and Lange-Nielsen syndrome). Over the past 10 to 20 years, the number of cases of inherited LQTS (Romano-Ward syndrome) has increased dramatically. It is doubtful that this reflects a true increase in incidence of disease due to a greater rate of sporadic gene mutations occurring in the heart or because of a rising incidence of consanguinity. Rather, the "incidence" of LQTS has risen because of the emerging awareness of and respect for this electrical malady in the heart. Understanding the principal elements of the LQTS, knowing the types of presentations, and being able to identify its presence electrocardiographically will allow the astute physician to expose this silent killer.

Adolescent↗