Biomedical subjects

L L Simpson

Publications and source records attributed to L L Simpson.

At least 19 recordsLinked to original sources

PubMed2006

Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome.

OBJECTIVE: To describe the frequency, risk factors, and outcome of intracerebral hemorrhage (ICH) in pregnancy and the postpartum period using a large database of US inpatient hospitalizations. METHODS: The authors obtained data from an administrative dataset, the Nationwide Inpatient Sample, which includes approximately 20% of all discharges from non-Federal hospitals, for the years 1993 through 2002. Women aged 15 to 44 years with a diagnosis of ICH were selected from the database for analysis, and within this group patients coded as pregnant or postpartum were identified. Using US Census data, estimates were made of the rates of ICH in pregnant/postpartum and non-pregnant women. Rates of various comorbidities in patients with pregnancy-related ICH were compared to the rates found in the general population of delivering patients using multivariate logistic regression to identify independent risk factors for pregnancy-related ICH. RESULTS: The authors identified 423 patients with pregnancy-related ICH, which corresponded to 6.1 pregnancy-related ICH per 100,000 deliveries and 7.1 pregnancy-related ICH per 100,000 at-risk person-years (compared to 5.0 per 100,000 person-years for non-pregnant women in the age range considered). The increased risk of ICH associated with pregnancy was largely attributable to ICH occurring in the postpartum period. The in-hospital mortality rate for pregnancy-related ICH was 20.3%. ICH accounted for 7.1% of all pregnancy-related mortality recorded in this database. Significant independent risk factors for pregnancy-related ICH included advanced maternal age (OR 2.11, 95% CI 1.69 to 2.64), African American race (OR 1.83, 95% CI 1.39 to 2.41), preexisting hypertension (OR 2.61, 95% CI 1.34 to 5.07), gestational hypertension (OR 2.41, 95% CI 1.62 to 3.59), preeclampsia/eclampsia (OR 10.39, 95% CI 8.32 to 12.98), preexisting hypertension with superimposed preeclampsia/eclampsia (OR 9.23, 95% CI 5.26 to 16.19), coagulopathy (OR 20.66, 95% CI 13.67 to 31.23), and tobacco abuse (OR 1.95, 95% CI 1.11 to 3.42). CONCLUSION: Intracerebral hemorrhage (ICH) accounts for a substantial portion of pregnancy-related mortality. The risk of ICH associated with pregnancy is greatest in the postpartum period. Advanced maternal age, African American race, hypertensive diseases, coagulopathy, and tobacco abuse were all independent risk factors for pregnancy-related ICH.

Adolescent↗

PubMed2001

The role of zinc binding in the biological activity of botulinum toxin.

Botulinum toxin is a zinc-dependent endoprotease that acts on vulnerable cells to cleave polypeptides that are essential for exocytosis. To exert this poisoning effect, the toxin must proceed through a complex sequence of events that involves binding, productive internalization, and intracellular expression of catalytic activity. Results presented in this study show that soluble chelators rapidly strip Zn(2+) from its binding site in botulinum toxin, and this stripping of cation results in the loss of catalytic activity in cell-free or broken cell preparations. Stripped toxin is still active against intact neuromuscular junctions, presumably because internalized toxin binds cytosolic Zn(2+). In contrast to soluble chelators, immobilized chelators have no effect on bound Zn(2+), nor do they alter toxin activity. The latter finding is because of the fact that the spontaneous loss of Zn(2+) from its coordination site in botulinum toxin is relatively slow. When exogenous Zn(2+) is added to toxin that has been stripped by soluble chelators, the molecule rebinds cation and regains catalytic and neuromuscular blocking activity. Exogenous Zn(2+) can restore toxin activity either when the toxin is free in solution on the cell exterior or when it has been internalized and is in the cytosol. The fact that stripped toxin can reach the cytosol means that the loss of bound Zn(2+) does not produce conformational changes that block internalization. Similarly, the fact that stripped toxin in the cytosol can be reactivated by ambient Zn(2+) or exogenous Zn(2+) means that productive internalization does not produce conformational changes that block rebinding of cation.

Animals↗

PubMed2000

Congenital heart disease: the impact of delivery in a tertiary care center on SNAP scores (scores for neonatal acute physiology).

OBJECTIVE: It has been hypothesized that delivery in a tertiary care center might improve the clinical condition and outcome of infants born with congenital heart disease. The purpose of this study was to determine the effect of delivery in a tertiary care center on SNAP scores (scores for neonatal acute physiology) of infants admitted to the neonatal intensive care unit with major structural cardiac defects. STUDY DESIGN: This retrospective cohort study included 195 infants with major congenital heart disease admitted to the neonatal intensive care unit at the New England Medical Center between July 1, 1992, and June 30, 1998. SNAP scores were abstracted from the medical record. The values of 97 neonates with major cardiac defects born at the New England Medical Center were compared with those of 98 neonates transferred to our center after delivery in a community setting. A 2-tailed Student t test for independent samples was used to compare the mean SNAP scores between the 2 cohorts. RESULTS: The SNAP scores for infants with major cardiac defects who were born at the New England Medical Center ranged from 0 to 41, with a mean of 10.6 +/- 8.8. The values for infants with congenital heart disease who were transferred to our center after birth in community-based hospitals ranged from 0 to 34, with a mean of 11.1 +/- 7.0. There was no significant difference between the 2 populations (P =.646). A comparison of the mean SNAP scores of infants with prenatally diagnosed disease who were delivered at our center versus infants with postnatally diagnosed disease who were delivered in community hospitals was also statistically not significant (P =.824). CONCLUSION: Delivery in a tertiary care center does not improve SNAP scores of infants with major structural cardiac defects.

Alprostadil↗

PubMed2000

Structural cardiac anomalies.

Although it is unrealistic to expect that all major structural cardiac anomalies will be detected at the time of routine prenatal ultrasound, an increase in prenatal diagnosis is anticipated as accreditation of ultrasound practices takes place nationwide. Following the diagnosis of congenital heart disease, evaluation for extracardiac anomalies and chromosomal abnormalities is important because these are found in up to 62% and 38% of prenatally identified cases, respectively. Although the literature is limited, counseling parents based on the prenatal experience gives them realistic information about frequency, diagnosis, associated findings, and prognosis of the heart defect found in their fetus. A multidisciplinary team of perinatologists, pediatric cardiologists, geneticists, pediatric cardiac surgeons, and neonatologists should be assembled to assist patients in making informed decisions about their pregnancies and to establish a reasonable management plan for ongoing pregnancies with congenital heart disease.

Diagnosis, Differential↗

PubMed2000

Fetal supraventricular tachycardias: diagnosis and management.

In the majority of cases, the diagnosis of an isolated fetal tachyarrhythmia results in a favorable perinatal outcome. Although there is general consensus on the management of fetal extrasystoles, refractory supraventricular tachycardia, and atrial flutter and fibrillation, the optimal approach to supraventricular tachycardia without hemodynamic compromise remains uncertain. The benefits of conservative management without antiarrhythmic therapy must be weighed carefully against the lack of reliable predictors for the development of fetal hydrops and associated neurologic complications.

Anti-Arrhythmia Agents↗

PubMed2000

Nuchal translucency and its relationship to congenital heart disease.

Nuchal translucency refers to the normal subcutaneous space, observed on first trimester ultrasound evaluation, between the skin and cervical spine. Increased nuchal translucency is known to be associated with an increased risk of aneuploidy, particularly Trisomy 21, and recent studies have also identified increased nuchal translucency as a nonspecific marker for various genetic syndromes and multiple structural anomalies, to include congenital heart disease. This increased risk applies to euploid and aneuploid pregnancies and is directly related to the degree of nuchal translucency thickening. This article reviews the role of nuchal translucency as a screening tool for congenital heart disease.

Aneuploidy↗

PubMed1999

Botulinum toxin as a carrier for oral vaccines.

Botulinum toxin is an unusually potent substance that acts on the nervous system to produce the clinical outcome of flaccid paralysis. To produce this effect, the toxin ordinarily proceeds through two separate but essential sequences of events. During the first, the toxin is ingested, it traverses a portion of the gastrointestinal system and then it is transcytosed from the lumen of the gut to the general circulation. During the second, circulating toxin binds to peripheral cholinergic nerve endings, it is endocytosed and then it acts as a metalloendoprotease to cleave polypeptides that are essential for exocytosis. Although botulinum toxin is antigenic, it ordinarily does not evoke an immune response during or after cases of oral poisoning. This is due to the fact that the dose of toxin that produces flaccid paralysis-and potentially death-is less than the dose needed to evoke an antibody response. In the recent past, the techniques of molecular biology have been used to generate an expression product of botulinum toxin that retains the ability to escape the gut and reach the general circulation, retains the ability to evoke an immune response, but has lost the ability to produce neurotoxicity. This modified toxin may have two clinical applications. The expression product itself may have utility as an oral vaccine against botulism. Beyond this, the modified toxin, or a truncation mutant of the toxin, may have utility as a carrier in the construction of other oral vaccines. Both potential applications could lead to the expression of oral vaccines in common foods.

Animals↗

PubMed1999

Botulinum toxin: potent poison, potent medicine.

Botulinum toxin is now used to treat a wide variety of cholinergic disorders, ranging from mild tics to more disabling forms of dystonia. The demonstrated safety of such treatments has encouraged further exploitation of the toxin's unique properties. With genetic manipulation of structural features, this poisonous substance could turn out to be an efficient carrier of oral medications and vaccines.

Anti-Dyskinesia Agents↗

PubMed1999

Pure botulinum neurotoxin is absorbed from the stomach and small intestine and produces peripheral neuromuscular blockade.

Clostridium botulinum serotype A produces a neurotoxin composed of a 100-kDa heavy chain and a 50-kDa light chain linked by a disulfide bond. This neurotoxin is part of a ca. 900-kDa complex, formed by noncovalent association with a single nontoxin, nonhemagglutinin subunit and a family of hemagglutinating proteins. Previous work has suggested, although never conclusively demonstrated, that neurotoxin alone cannot survive passage through the stomach and/or cannot be absorbed from the gut without the involvement of auxiliary proteins in the complex. Therefore, this study compared the relative absorption and toxicity of three preparations of neurotoxin in an in vivo mouse model. Equimolar amounts of serotype A complex with hemagglutinins, complex without hemagglutinins, and purified neurotoxin were surgically introduced into the stomach or into the small intestine. In some experiments, movement of neurotoxin from the site of administration was restricted by ligation of the pylorus. Comparison of relative toxicities demonstrated that at adequate doses, complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin can be absorbed from the stomach. The potency of neurotoxin in complex was greater than that of pure neurotoxin, but the magnitude of this difference diminished as the dosage of neurotoxin increased. Qualitatively similar results were obtained when complex with hemagglutinins, complex without hemagglutinins, and pure neurotoxin were placed directly into the intestine. This work establishes that pure botulinum neurotoxin serotype A is toxic when administered orally. This means that pure neurotoxin does not require hemagglutinins or other auxiliary proteins for absorption from the gastrointestinal system into the general circulation.

Absorption↗

PubMed1999

Characterization of a vertebrate neuromuscular junction that demonstrates selective resistance to botulinum toxin.

Botulinum toxin blocks transmitter release by proceeding through a series of four steps: binding to cell surface receptors, penetration of the cell membrane by receptor-mediated endocytosis, penetration of the endosome membrane by pH-induced translocation, and intracellular proteolysis of substrates that govern exocytosis. Each of these steps is essential for toxin action on intact cells. Therefore, alterations in cell structure or cell function that impede any of these steps should confer resistance to toxin. In the present study, screening for susceptibility to four serotypes of botulinum toxin revealed that the cutaneous-pectoris nerve-muscle preparation of Rana pipiens is resistant to type B botulinum toxin. Resistance was demonstrated both by electrophysiologic techniques and by dye-staining techniques. In addition, resistance to serotype B was demonstrated at toxin concentrations that were 2 orders of magnitude higher than those associated with blockade produced by other serotypes. In experiments on broken cell preparations, type B toxin cleaved synaptobrevin from frog brain synaptosomes. However, the toxin did not bind to frog nerve membranes. These findings suggest that resistance is due to an absence of cell surface receptors for botulinum toxin type B. The fact that cutaneous-pectoris preparations were sensitive to other botulinum toxin serotypes (A, C, and D), as well as other neuromuscular blocking agents (alpha-latrotoxin, beta-bungarotoxin), indicates that botulinum toxin type B receptors are distinct.

Animals↗

PubMed1998

Binding and transcytosis of botulinum neurotoxin by polarized human colon carcinoma cells.

T-84 and Caco-2 human colon carcinoma cells and Madin-Darby canine kidney (MDCK) cells were used to study binding and transcytosis of iodinated Clostridium botulinum neurotoxin serotypes A, B, and C, as well as tetanus toxin. Specific binding and transcytosis were demonstrated for serotypes A and B in intestinal cells. Using serotype A as an example, the rate of transcytosis by T-84 cells was determined in both apical to basolateral (11.34 fmol/h/cm2) as well as basolateral to apical (8.98 fmol/h/cm2) directions, and by Caco-2 cells in the apical to basolateral (8.42 fmol/h/cm2) direction. Serotype A retained intact di-chain structure during transit through T-84 or Caco-2 cells, and when released on the basolateral side was toxic in vivo to mice and in vitro on mouse phrenic nerve-hemidiaphragm preparations. Serotype C and tetanus toxin did not bind effectively to T-84 cells, nor were they efficiently transcytosed (8-10% of serotype A). MDCK cells did not bind or efficiently transcytose (0.32 fmol/h/cm2) botulinum toxin. Further characterization demonstrated that the rate of transcytosis for serotype A in T-84 cells was increased 66% when vesicle sorting was disrupted by 5 microM brefeldin A, decreased 42% when microtubules were disrupted by 10 microM nocodazole, and decreased 74% at 18 degreesC. Drugs that antagonize toxin action at the nerve terminal, such as bafilomycin A1 (which prevents acidification of endosomes) and methylamine HCl (which neutralizes acidification of endosomes), produced only a modest inhibitory effect on the rate of transcytosis (17-22%). These results may provide an explanation for the mechanism by which botulinum toxin escapes the human gastrointestinal tract, and they may also explain why specific serotypes cause human disease and others do not.

Animals↗

PubMed1998

Acute fatty liver of pregnancy in triplet gestation.

BACKGROUND: Acute fatty liver is reported to be more common in twin than in singleton pregnancies. We report three cases of biopsy-proven acute fatty liver in triplet gestations. CASES: In all three cases of acute fatty liver complicating triplet pregnancies, the presenting features were vague abdominal complaints with elevated hepatic aminotransferase levels. A liver biopsy was performed in each case, and cesareans were performed immediately after the diagnosis was confirmed histologically. Clinical resolution occurred in all cases, and all infants did well in the neonatal period. CONCLUSION: Patients with triplet gestations should be monitored closely for the early signs of acute fatty liver. Triplet gestations may contribute to the onset of acute fatty liver by further stressing the fatty acid oxidation capabilities of the susceptible woman.

Acute Disease↗

PubMed1998

Cardiac dysfunction in twin-twin transfusion syndrome: a prospective, longitudinal study.

OBJECTIVE: To use serial echocardiography to evaluate prospectively the cardiac dysfunction in twin-twin transfusion syndrome and determine its clinical course and outcome. METHODS: Twin pregnancies presenting in the second trimester with sonographic evidence of twin-twin transfusion syndrome were managed with therapeutic reduction amniocenteses. Gestational age at diagnosis and delivery, number of amniocenteses performed, volume of amniotic fluid withdrawn, placentation, birth weight, hemoglobin at delivery, and perinatal outcome were recorded. Serial fetal echocardiography was carried out in a single tertiary center. Echocardiographic assessments included cardiac anatomy, chamber size, cardiothoracic ratio, interventricular septal thickness, ventricular systolic function, and the presence and severity of atrioventricular valve regurgitation. Postnatal echocardiograms were obtained on the surviving twins. RESULTS: Twelve cases of twin-twin transfusion syndrome were evaluated with serial echocardiography. Evidence of cardiac dysfunction was present prenatally in 10 recipient twins. All of the donor twins had normal fetal echocardiographic assessments. The most common abnormalities detected prenatally in recipient twins were decreased ventricular function, tricuspid regurgitation, and cardiac chamber enlargement. A deterioration of cardiac function was observed in seven recipient twins with increasing gestational age. Four of the eight surviving recipient twins had persistent postnatal echocardiographic abnormalities on follow-up examinations after the first 28 days of life. CONCLUSION: Prenatal cardiac dysfunction is common in recipient twins and can be transient, progressive, or persistent beyond the neonatal period.

Female↗

PubMed1998

Cost issues surrounding the use of computerized telemedicine for obstetric ultrasonography.

OBJECTIVE: The purpose of this study was to describe the cost implications of converting an established videotape review network for obstetric ultrasonography to one based on telemedicine technology. DESIGN: Retrospective review of fixed and non-fixed costs associated with interpreting obstetric ultrasound examinations using both videotape and telemedicine transmission. SUBJECTS: A network of three community offices transmitting 600 obstetric ultrasound examinations per month to a central tertiary level facility. METHODS: Sonographers at the community offices record ultrasound examinations onto videotape, which are then sent by courier to a central facility for interpretation. At the completion of this videotaped examination, sonographers repeat the ultrasound scan while transmitting real-time images over a telemedicine link to the central facility. Costs associated with the videotape review technique that can be avoided by converting to telemedicine interpretation were derived and compared with the fixed and non-fixed costs associated with establishing the telemedicine network. RESULTS: For this network, the fixed costs for establishing telemedicine are $101,750. Monthly non-fixed cost savings by eliminating videotape review include $1620 to $2700 for printing still images, $1200 for courier charges and $7000 for fewer repeat ultrasound examinations. Monthly non-fixed costs for the telemedicine network are $2415. Net monthly savings in non-fixed costs for a telemedicine network are therefore $7405 to $8585, which may pay for the initial fixed costs in 12 to 14 months. CONCLUSIONS: The high cost of a telemedicine network may be offset by possible savings in non-fixed costs compared with alternative systems for interpreting obstetric ultrasonography.

Costs and Cost Analysis↗

PubMed1997

Validation of fetal telemedicine as a new obstetric imaging technique.

OBJECTIVE: Our purpose was to establish whether obstetric ultrasonography interpreted by a live video telemedicine link is comparable to interpretation by videotape review in a low-risk patient population. STUDY DESIGN: An Integrated Services Digital Network (ISDN 6) was established from three satellite offices to our central prenatal diagnostic center. Patients seen at these satellite offices had a complete fetal anatomic survey recorded onto videotape by a trained ultrasonographer. A live interactive video telemedicine link was then established to our center by the digital network, and a perinatologist directed the ultrasonographer through the anatomy survey. Subsequently a different perinatologist, blinded to the telemedicine interpretation, reviewed the videotaped examination. The reports from the videotaped and telemedicine scans were then compared on the basis of a score of 33 anatomic items. RESULTS: The first 200 patients seen at the satellite offices were included. Telemedicine and videotape interpretations provided similar scores in 84% of scans. In 17 of the 33 anatomic categories telemedicine provided significantly better scores than videotape, whereas in the remaining 16 anatomic categories the scores were equivalent. More videotape than telemedicine examinations required repeat ultrasonography because of suboptimal imaging (10% vs 3%, p = 0.003). CONCLUSIONS: The interpretation of obstetric ultrasonography with use of live video telemedicine is comparable to videotape review. Fetal telemedicine may prove to be a useful tool for providing ultrasonographic interpretation of fetal anatomy to a network of low-risk obstetric practices.

Feasibility Studies↗

PubMed1997

Validation of first-trimester telemedicine as an obstetric imaging technology: a feasibility study.

OBJECTIVE: To establish whether first-trimester obstetric ultrasonography interpreted by a live video telemedicine link is comparable to an established videotape review network in a low-risk patient population. METHODS: An integrated services digital network was established from three satellite offices to our central prenatal diagnostic center. All patients had a sonographic evaluation of the uterus, adnexa, and gestational sac recorded onto videotape by a trained sonographer. A live, interactive video telemedicine link was established, and a perinatologist directed the sonographer through the scan. Subsequently, a different perinatologist, blinded to the telemedicine interpretation, reviewed the original videotaped examination. The reports generated from both modalities then were compared by means of a score of 12 sonographic characteristics. RESULTS: The first 100 patients were included. The mean gestational age (+/-standard deviation) was 8.9 +/- 2.3 weeks (range 5.7-14.4), and the mean duration for telemedicine scans was 7.8 +/- 2.9 minutes (range 3.8-20.1). Telemedicine and videotape review scores were the same in 95 cases, and the final diagnosis was identical in 98 cases. This study had 80% power to detect a 10% difference in diagnosis at a significance level of .05. The ability to detect abnormalities was equivalent using both systems. CONCLUSION: The interpretation of first-trimester obstetric ultrasonography using live video telemedicine is equivalent to a system of videotape review. Obstetric telemedicine may prove to be a useful tool for providing sonographic imaging for low-risk obstetric patients.

Feasibility Studies↗

PubMed1997

Induction of an immune response by oral administration of recombinant botulinum toxin.

A gene encoding the full-size botulinum neurotoxin serotype C was reconstructed in vector pQE-30 and expressed at high levels in Escherichia coli. Three amino acid mutations (H229-->G, E230-->T, and H233-->N) were generated in the zinc-binding motif, resulting in complete detoxification of the modified recombinant holotoxin. The PCR-amplified wild-type light chain of botulinum neurotoxin serotype C was also expressed in E. coli and used as a control in all experiments. Modified recombinant holotoxin and light chain contained a histidine affinity tag at the amino terminus, which was used for detection and purification. Recombinant proteins were purified on nickel affinity resin and analyzed by Western blotting with the anti-histidine tag and anti-neurotoxin C antibodies. The results indicated that the 150-kDa molecule of modified recombinant holotoxin and the 50-kDa recombinant light chain were synthesized without degradation; however, E. coli did not provide for efficient nicking of modified recombinant toxin. Modified recombinant holotoxin was not toxic to mice, had no effect on nerve-evoked muscle twitch in vitro, and was not able to cleave syntaxin in crude synaptosome preparations. The recombinant light chain was also nontoxic in vivo, had no effect on evoked muscle twitch, but was able to cleave syntaxin. Modified recombinant neurotoxin and light chain were administered to animals either orally or subcutaneously. Both oral administration and subcutaneous administration of modified recombinant neurotoxin evoked high levels of serum antibodies and protective immunity. Oral administration of recombinant light chain evoked no systemic response, whereas subcutaneous administration evoked antibody production and immunity.

Administration, Oral↗

PubMed1997

Expression of botulinum toxin binding sites in Xenopus oocytes.

The binding of iodinated botulinum toxin type B to nerve membranes was studied by using rat and mouse preparations. The toxin was examined both in the single-chain and in the proteolytically processed dichain form, and binding sites both in the spinal cord and in various brain regions were assayed. Rat and mouse brains possessed specific binding sites for botulinum toxin type B. The average Kd values for the various rat and mouse membrane preparations examined were 4.2 +/- 0.7 nM and 3.7 +/- 0.9 nM, respectively. The average Bmax values for the same tissue preparations were 7.3 +/- 0.7 pmol/mg of protein and 7.5 +/- 1.9 pmol/mg protein, respectively. The binding of botulinum toxin type B to rat brain membranes was not antagonized by a polyclonal antibody against the cytosolic domain of synaptotagmin 1 or by a monoclonal antibody directed against the luminal domain of synaptotagmin 1. In addition, these antibodies did not protect the mouse phrenic nerve-hemidiaphragm from toxin-induced neuromuscular blockade. Extraction of whole-brain mRNA and injection into Xenopus oocytes led to expression of binding sites for botulinum toxin. Extraction and injection of cerebellar mRNA led to expression of a higher density of binding sites. The number of binding sites was not diminished when oocytes were pretreated with antibodies against the cytosolic and luminal domains of synaptotagmin 1. These findings are likely to aid in the isolation, characterization, and reconstitution of toxin binding sites.

Animals↗