The Way It Was.

Mary Osborn was a native Californian. She was an undergraduate at the University of California, Berkeley, where she worked in the laboratory of I.L. Chaikoff. She received her PhD at the University of Washington, where her work on the role of folic acid coenzymes in one-carbon metabolism revealed the mechanism of action of methotrexate. After postdoctoral training with Bernard Horecker in the Department of Microbiology at New York University (NYU), she embarked on her research career as a faculty member in the NYU Department of Microbiology and in the Department of Molecular Biology at Albert Einstein College of Medicine. In 1968 she moved as one of the founding faculty of the new medical school of the University of Connecticut, where she remained until her retirement in 2014. Her research was focused on the biosynthesis of the endotoxin lipopolysaccharide (LPS) of gram-negative bacteria and on the assembly of the bacterial cell envelope. She made seminal contributions in these areas. She was the recipient of numerous honors and served as president of several important scientific organizations. Later in her career she served as chair of the National Research Council Committee on Space Biology and Medicine, advisory to the National Aeronautics and Space Administration (NASA), which produced an influential report that plotted the path for NASA's space biology research program in the first decade of the twenty-first century. Dr. Osborn died on Jan. 17, 2019.

Breath-holding spells associated with significant bradycardia: successful treatment with permanent pacemaker implantation.

OBJECTIVE: To determine whether children with pallid breath-holding spells associated with bradycardia can be treated safely and successfully with permanent pacemaker implantation. METHODS: The records of pediatric patients who had apparent breath-holding spells and associated bradycardia and were treated with permanent pacemaker implantation were reviewed. RESULTS: Ten pediatric patients with apparent breath-holding spells associated with bradycardia were treated with a permanent ventricular demand pacemaker at the Mayo Clinic between 1985 and 1995. Patients had onset of symptoms between ages 6 days and 12 months and presented for evaluation between ages 12 months and 5 years. Duration of spells was 15 seconds to 10 minutes. Medications to prevent spells were unsuccessful. Electrocardiograms documented asystolic pauses of 1.7 to 24 seconds (mean: 11.9 seconds). Permanent ventricular demand pacemakers were implanted at 10 months to 5 years of age (median: 14.5 months): 9 endocardial and 1 epicardial. Three patients required pacemaker revision. At follow-up of 38 to 170 months (median: 65.5), 5 patients had complete resolution of spells, 2 had only mild color change without loss of consciousness or seizure activity, and 3 continued to have minor brief spells. CONCLUSIONS: Permanent pacemaker therapy for children with pallid breath-holding spells associated with severe bradycardia is safe, efficacious, and warranted.

Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome?

Inappropriate sinus tachycardia and postural orthostatic tachycardia are ill-defined syndromes with overlapping features. Although sinus node modification has been reported to effectively slow the sinus rate, long-term clinical response has not been adequately assessed. Furthermore, whether patients with postural orthostatic tachycardia would benefit from sinus node modification is unknown. The study prospectively assessed the short- and long-term clinical outcomes of seven consecutive female patients with postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia who were treated with sinus node modification. The study was conducted in a tertiary care center. The electrophysiological and clinical responses were prospectively assessed as defined by autonomic function testing, including Valsalva maneuver, deep breathing, tilt table testing, and quantitative sudomotor axonal reflex testing. Among the study population (mean age was 41+/-6 years), 5 (71%) patients had successful sinus node modification. At baseline, heart rates were 101+/-12 beats/min before modification and 77+/-9 beats/min after modification (P = 0.001). With isoproterenol, heart rates were 136+/-9 and 105+/-12 beats/min (P = 0.002) before and after modification, respectively. The mean heart rate during 24-hour Holter monitoring was also significantly reduced: 96+/-9 and 72+/-6 beats/min (P = 0.005) before and after modification, respectively. Despite the significant reduction in heart rate, autonomic symptom score index (based on ten categories of clinical symptoms) was unchanged before (15.6+/-4.1) and after (14.6+/-3.6) sinus node modification (P = 0.38). Sinus rate can be effectively slowed by sinus node modification. Clinical symptoms are not significantly improved after sinus node modification in patients with inappropriate sinus tachycardia and postural orthostatic tachycardia. A primary subtle autonomic disregulation is frequently present in this population. Sinus node modification is not recommended in this patient population.

Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations.

The neurofibromatosis type 1 (NF1) gene located at 17q 11.2 contains 60 exons and spans 350 kb of genomic DNA. Mutation analysis has been hampered by the large size of the gene, the high rate of new mutations, a lack of mutational clustering and the presence of numerous homologous loci. Mutation detection methods based on the direct analysis of a gene's RNA transcript permit the rapid screening of large multi-exonic genes. However, the detection of frame-shift or nonsense mutations can be limited by instability of the mutant mRNA species due to nonsense-mediated decay. In order to determine the frequency of this allelic exclusion, total lymphocyte RNA was analysed from 15 NF1 patients with known truncating mutations and a panel of 40 NF1 patients with unknown mutations. The level of expression of the mutant message was greatly reduced in 2 of the 15 samples (13%), and 3 of the 18 informative samples from the panel of 40. A coupled reverse-transcription polymerase chain reaction and protein truncation test method was subsequently applied to screen RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide bands were identified and characterised in 21 samples (53%). The mutations identified were 479del107;ins31, 495delTGTT, 1127delTGAT, R416X, R440X, 1446del 62, 1541delAG, 2252del 74, 2537insTG, 3456delACTC, R1276X, R1362X, 5749ins171, 6084del280, 6487insA, R2214X, 6791insA, 6858del141, 7458delC, 7676 2A-G and 8081delC. These mutations were uniformly distributed across the gene and 14 represent novel changes that contribute to the germline mutational spectrum of the NF1 gene.

Arrhythmogenic right ventricular dysplasia masquerading as dilated cardiomyopathy.

This is a case report of 2 patients with severe left ventricular dysfunction and ventricular arrhythmias. At the time of cardiac transplantation they were found to have right ventricular dysplasia with left ventricular involvement.

Effects of slow pathway ablation on fast pathway function in patients with atrioventricular nodal reentrant tachycardia.

INTRODUCTION: This study investigated whether fast pathway conduction properties are altered by slow pathway ablation in patients with AV nodal reentrant tachycardia. METHODS AND RESULTS: Forty consecutive patients who underwent successful ablation of the slow pathway were prospective subjects for the study. Isoproterenol was used to enhance conduction and to differentiate interactive mechanisms. Potential electrotonic interactions were assessed by comparing patients with and those without residual dual AV node physiology after slow pathway ablation. Paired and unpaired t-tests were used when appropriate P < 0.05 was considered statistically significant. In the entire study population, heart rates were not significantly different before and after slow pathway ablation (RR = 770 +/- 114 msec before and 745 +/- 99 msec after, P = 0.07). Anterograde fast pathway conduction properties were unchanged after slow pathway ablation (effective refractory period, 348 +/- 84 msec before and 336 +/- 86 msec after, P = 0.13; shortest 1:1 conduction, 410 +/- 93 msec before and 400 +/- 82 msec after, P = 0.39). Retrograde fast pathway characteristics also were similar before and after ablation. Neither anterograde nor retrograde fast pathway conduction properties during isoproterenol infusion were changed by slow pathway ablation. When the study population was further divided into patients with (n = 13) or without (n = 27) residual dual AV node physiology, no significant change was detected in fast pathway function in either group after slow pathway ablation. CONCLUSIONS: Fast pathway conduction characteristics were not affected by slow pathway ablation. In patients with AV nodal reentrant tachycardia, observations suggest that fast and slow pathways are functionally distinct.

Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders. It is caused by mutations in the NF1 gene which comprises 60 exons and is located on chromosome 17q. The NF1 gene product, neurofibromin, displays partial homology to GTPase-activating protein (GAP). The GAP-related domain (GRD), encoded by exons 20-27a, is the only region of neurofibromin to which a biological function has been ascribed. A total of 320 unrelated NF1 patients were screened for mutations in the GRD-encoding region of the NF1 gene. Sixteen different lesions in the NF1 GRD region were identified in a total of 20 patients. Of these lesions, 14 are novel and together comprise three missense, two nonsense and three splice site mutations plus six deletions of between 1 and 4 bp. The effect of one of the missense mutations (R1391S) was studied by in vitro expression of a site-directed mutant and GAP activity assay. The mutant protein, R1391S, was found to be some 300-fold less active than wild-type NF1 GRD. The mutations reported in this study therefore provide further material for the functional analysis of neurofibromin as well as an insight into the mutational spectrum of the NF1 GRD.

Adenosine: potential modulator for vasovagal syncope.

OBJECTIVES: This study examined the hypothesis that adenosine could provoke a vasovagal response in susceptible patients. Mechanisms of the vasovagal response were further explored by studying the adenosine-mediated reactions. BACKGROUND: Increased sympathetic activity is frequently observed before vasovagal syncope. Recent studies have demonstrated that adenosine, in addition to its direct bradycardiac and vasodilatory effects, can increase sympathetic discharge by activating cardiovascular afferent nerves. METHODS: The effects of adenosine and head-up tilt-table testing with or without isoproterenol were prospectively evaluated in 85 patients examined for syncope after negative results of electrophysiologic testing (51 men and 34 women, mean [+/- SD] age 61 +/- 17 years). Adenosine bolus injections of 6 mg and 12 mg were sequentially administered to patients in the upright position. The same protocol was implemented in 14 normal control subjects (7 men and 7 women, mean [+/- SD] age 38 +/- 10 years). RESULTS: Transient hypertension or tachycardia was observed in 57 (67%) and 20 (24%) patients after administration of 6 mg and 12 mg of adenosine, respectively, during the immediate phase (first 15 s), suggesting direct sympathetic activation. Hypotension and reflex tachycardia were observed in all patients during the delayed phase (15 to 60 s after adenosine injection), suggesting baroreceptor unloading. A vasovagal response was induced in 22 (26%) and 29 (34%) patients after adenosine administration and during tilt-table testing. Inducibility of a vasovagal response by these two methods was comparable (p = 0.12). Of the control subjects, one (7%) had a vasovagal response after adenosine administration and one (7%) had a positive response during tilt-table testing. CONCLUSIONS: These observations support the idea that adenosine is an endogenous modulator of the cardiac excitatory afferent nerves. Sympathetic activation by adenosine can be direct (i.e., cardiac excitatory afferent nerves) and indirect (i.e., vasodilation and reflex sympathetic activation). Adenosine could be an important modulator in triggering a vasovagal response in susceptible patients during examination for syncope.

Extraction of the Telectronics Accufix 330-801 atrial lead: the Mayo Clinic experience.

OBJECTIVE: To document a cumulative experience with removal of the Telectronics 330-801 Accufix atrial lead after it was withdrawn from the market. DESIGN: We reviewed our results with 96 attempted lead extraction procedures through Dec. 1, 1995. MATERIAL AND METHODS: All patients underwent preoperative assessment, including fluoroscopic screening of the lead. Patients had blood typing and screening done before the extraction procedure, and extractions were performed with cardiac surgical intervention available. Pacing dependence was assessed to determine the need for temporary pacing. RESULTS: The mean patient age was 65.7 +/- 1.6 years and the mean duration of lead implantation was 31.0 +/- 1.4 months. Of the 96 lead extractions attempted, 94 were successful. Of the 96 cases, the retention wires were normal in 29, fractured without protrusion in 34, and fractured with protrusion in 33. Fifty-three leads were removed with use of simple traction only, and seven leads were removed by using a locking stylet and telescoping sheaths. The Cook workstation was used in the removal of 32 leads through the femoral vein; in 1 of these 32 patients, the retention wire was removed before lead extraction. The retention wire was removed but the lead was left intact in one patient. One lead was removed during an opertive maze procedure. Associated complications were minimal. CONCLUSION: Although lead extraction is a potentially fatal procedure, the Telectronics 330-801 Accufix atrial lead can be extracted safely with minimal morbidity when performed by experienced personnel.

Familial sudden death syndrome with an abnormal signal-averaged electrocardiogram as a potential marker.

Most familial sudden cardiac death syndromes are associated with structural heart disease or 12-lead electrocardiographic abnormalities. Additionally, the utility of signal-averaged electrocardiograms in patients with familial sudden death syndromes has not been examined. We studied a kindred with sudden death to determine whether they could be classified into any of the previously described syndromes and whether an abnormal signal-averaged electrocardiogram is a marker for this trait. Surviving family members had normal 12-lead electrocardiograms and echocardiograms. Two of the patients who died from ventricular arrhythmias had normal hearts on autopsy. Two surviving family members had a clinical history of arrhythmic events; both had abnormal signal-averaged electrocardiograms and inducible ventricular arrhythmias during electrophysiologic studies. The other family members had normal signal-averaged electrocardiograms. This familial sudden death syndrome appears to be unique because the patients have anatomically normal hearts and normal 12-lead electrocardiograms. An abnormal signal-averaged electrocardiogram may be a marker for the sudden death trait.

Multicenter experience with a bipolar tined polyurethane ventricular lead.

A multicenter study was undertaken to determine the failure rate of a specific bipolar tined polyurethane ventricular pacing lead, the Medtronic 4004/4004M pacing lead. Seven centers in the United States and Canada implanted 586 Medtronic 4004/4004M pacing leads. The study was designed to determine the probability and clinical manifestations of lead failure. Only failures compatible with an insulation problem were included. The Kaplan-Meier estimate of the percentage of 4004/4004M lead failures within 4 years after implantation was 14.1% (95% confidence interval: 8.5%-19.3%). Failures were manifested as sensing abnormalities, failure to capture, early battery depletion, and significant decrease in measured impedance compared with previous impedance measurements. The observed rate of failure is unacceptable, and strong consideration should be given to replacing the 4004/4004M pacing lead in pacemaker dependent patients and closely monitoring nondependent patients.

Consistent subcutaneous prepectoral implantation of a new implantable cardioverter defibrillator.

OBJECTIVE: To describe the use of a new implantable cardioverter defibrillator (ICD) that can be placed in the prepectoral region rather than implanted in the abdominal wall. DESIGN: We report the experience of placement of this new ICD in the prepectoral region in 13 patients from Sept. 28, 1993, through Jan. 10, 1994, at the Mayo Clinic. MATERIAL AND METHODS: Thirteen consecutive patients offered this new ICD underwent placement of transvenous defibrillation leads, and the pulse generator was placed in a pocket formed in the subcutaneous, prepectoral space. Testing ensured a defibrillation threshold of 24 J or less. RESULTS: In all 13 patients, the pulse generator could be placed in the subcutaneous, prepectoral space. In all except one patient, acceptable defibrillation thresholds were achieved by using lead systems placed totally transvenously. Only one patient required placement of a subcutaneous patch. All but two patients were dismissed from the hospital within 3 days after the ICD implantation. CONCLUSION: Consistent subcutaneous, prepectoral placement of this new ICD pulse generator is possible. Because the entire procedure can be performed in the pacemaker implantation room, the potential exists for decreasing the duration of the hospitalization and associated costs.

The Dotter retriever and pigtail catheter: efficacy in extraction of chronic transvenous pacemaker leads.

Several techniques exist for percutaneous extraction of chronic pacemaker leads. To establish the efficacy of the Dotter retriever and pigtail catheter, we reviewed the removal of 59 endocardial pacemaker leads in 42 patients (mean age 71 years). The mean duration of lead implantation was 44 months (range 1-169 months). Thirty-two leads were withdrawn with simple traction alone, and five leads were abandoned when traction failed. The remaining 22 leads were manipulated with a Dotter retriever or pigtail catheter, or both. Twelve leads were dislodged from the endocardium with simple traction (10) or with traction transmitted through an entwining pigtail catheter (2), but they could not be fully withdrawn. Eleven of these leads (92%) were then successfully extracted with the Dotter retriever. Seven of the remaining 10 leads were successfully dislodged and removed by the Dotter retriever. Overall, 9 of 12 leads (75%) that could not be dislodged from the endocardium with simple traction were removed with a Dotter retriever or pigtail catheter, or both. Three patients in whom no catheter method worked required thoracotomy for removal of infected leads. No complications resulted from use of the Dotter retriever or pigtail catheter. We conclude that the Dotter retriever and pigtail catheter have moderate efficacy for dislodging chronic endocardial leads. Once mobilized, however, the leads can be withdrawn with great success with the Dotter retriever. Newer technology should not result in the abandonment of this proven technique.

A multicenter experience with a bipolar tined polyurethane ventricular lead.

A multicenter study was undertaken to determine the failure rate of a specific polyurethane bipolar tined pacing lead, the Medtronic 4012 pacing lead. Six centers in the United States and Canada implanted 1,190 Medtronic 4012 pacing leads. The study was designed to determine the probability and clinical manifestations of lead failure. Only failures compatible with an insulation problem were included. The probability of a 4012 lead failure by Kaplan-Meier analysis was 20.9% at 6 years after implantation. Failures were manifested as sensing abnormalities, failure to capture, early battery depletion, and significant decrease in measured impedance compared with the previous impedance measurements. Of the 95 definite lead failures, 16 (16.8%) were associated with symptoms similar to those experienced before pacemaker placement. The observed failure rate is unacceptable, and strong consideration should be given to replacing the 4012 pacing lead in pacemaker-dependent patients and closely monitoring nondependent patients.

Pyopneumopericardium attributed to an esophagopericardial fistula: report of a survivor and review of the literature.

Herein we describe a case of pyopneumopericardium that resulted from formation of an acquired esophagopericardial fistula in a patient with silent, benign esophageal ulcer disease. Atypical features on initial examination suggested congestive heart failure or a pneumonic process (or both). The delayed development of pneumopericardium disclosed on a chest roentgenogram led to the clinical recognition of the esophagopericardial fistula. Subsequent emergent pericardiocentesis relieved cardiac tamponade and enabled us to diagnose pyopneumopericardium. A radiographic contrast study with use of meglumine diatrizoate revealed the site of the fistula in the midesophagus. The esophagopericardial fistula was surgically closed, and our patient had a good final result. Formation of an esophagopericardial fistula is a relatively uncommon finding; of the 60 previously reported cases, only 10 patients have survived. As illustrated in the current case, early diagnosis and treatment, including pericardial drainage and intense antibiotic therapy followed by a well-planned operative closure of the fistula, are paramount for the successful management of esophagopericardial fistulas.

Energy dependence of O-antigen synthesis in Salmonella typhimurium.

The uncoupler 2,4-dinitrophenol prevents in vivo synthesis of O antigen in Salmonella typhimurium by inhibiting the first reaction of the pathway, formation of galactosyl-pyrophosphoryl-undecaprenol. Inhibition was observed only in intact cells; dinitrophenol had no effect on activity of the synthase enzyme in isolated membrane fractions. In vivo inhibition could not be explained by changes in intracellular nucleotide pools or a shift in the equilibrium of the reaction and appeared to be specific for the first step in the pathway. Neither the subsequent mannosyl transferase, which catalyzes formation of the trisaccharide-lipid intermediate, mannosyl-rhamnosyl-galactosyl-pyrophosphoryl-undecaprenol, nor O-antigen polymerase was inhibited. In addition, incorporation of galactose into core lipopolysaccharide was only modestly inhibited under conditions in which O-antigen synthesis was abolished. The results suggest that maintenance of proton motive force is required for access of substrate, UDP-galactose and/or undecaprenyl phosphate, to the active site of the galactosyl-pyrophosphoryl-undecaprenol synthase enzyme.

Evidence for energy-dependent transposition of core lipopolysaccharide across the inner membrane of Salmonella typhimurium.

The uncoupler 2,4-dinitrophenol blocks the final step of lipopolysaccharide assembly--transfer of O antigen from undecaprenyl pyrophosphate to core lipopolysaccharide--in intact Salmonella typhimurium but not in isolated membrane fractions. The O-antigen ligase enzyme is not inhibited by dinitrophenol in vitro, and core lipopolysaccharide synthesized in the presence of uncoupler in vivo is functional as acceptor of O antigen in vitro. The evidence strongly suggests that maintenance of proton motive force is required for transmembrane transposition of core lipopolysaccharide to the active site of O-antigen ligase at the periplasmic face of the inner membrane.

Molecular heterogeneity at the phenylalanine hydroxylase locus in the population of the south-west of England.

The phenylalanine hydroxylase gene locus has been studied in 35 independent phenylketonuric families in the south-west of England using RFLP haplotype patterns and allele specific oligonucleotide probes. Haplotype 3 was the most common pattern on mutant chromosomes and there was strict linkage disequilibrium between this haplotype and the splice mutation in exon 12. The R408W mutation in exon 12 occurred on both haplotypes 1 and 2. The R126Q mutation in exon 7 was found only on a rare haplotype 28 pattern. No gene carried the R158Q mutation. More than 60% of mutant genes did not carry these four mutations which were originally described in other European populations. We suggest that the splice mutation arose as a single event and spread throughout northern Europe by population migration and admixture. In addition, we believe the haplotype/mutation associations seen in our population are a reflection of the mixed ancestry of the inhabitants of the British Isles.

Antitachycardia pacemaker treatment of postoperative arrhythmias in pediatric patients.

An automatic antitachycardia pulse generator (Intertach 262-12) was implanted in each of six pediatric patients (mean age, 10 years) with drug-resistant and persistent postoperative supraventricular arrhythmias. Four had bradycardia-tachycardia syndrome, two after a Mustard procedure for transposition of the great arteries, one after a Senning procedure for the same anomaly, and one after a Fontan procedure for univentricular heart with transposition of the great arteries. Of the two remaining patients, one had atrial flutter after a modified Fontan procedure for univentricular heart and one had intra-atrial reentry tachycardia after a modified Fontan procedure for double-outlet right ventricle with pulmonary stenosis. During a mean follow-up interval of 31 months after implantation, pacemakers were activated on multiple occasions and functioned appropriately in all six patients. Complications necessitated six invasive interventions in three patients: erosion or infection of the system, adaptor fracture, and connector block fracture on one occasion each and lead dislodgment on three occasions. Four of the six patients continued to take drugs at the end of this study; however, all patients had their drug therapy reduced and one was taking digoxin only. The number of hospital admissions decreased after implantation. Despite a number of technical challenges, this newer multiprogrammable antitachycardia pacemaker appears to be a valuable addition to the treatment of refractory postoperative supraventricular tachyarrhythmias in pediatric patients.