Search PubMed⌕ Search

Biomedical subjects

L L Simpson

Publications and source records attributed to L L Simpson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Supraventricular tachycardia in the fetus: conservative management in the absence of hemodynamic compromise.

The purposes of this study were to assess the natural history of isolated fetal supraventricular tachycardia and to evaluate the role of conservative management without medical therapy in the absence of hemodynamic compromise. Spontaneous resolution of supraventricular tachycardia occurred in eight of nine fetuses followed expectantly with serial evaluations. These data suggest that the spontaneous resolution of isolated fetal supraventricular tachycardia may be a common occurrence. Although conservative management may prove to be a reasonable option for fetuses with isolated supraventricular tachycardia, this approach must be balanced against the lack of reliable predictors for the development of hemodynamic compromise.

Female↗
PubMed1997

In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches.

Human exposure to botulinum toxin typically occurs in two settings: 1) as an etiologic agent in the disease botulism and 2) as a therapeutic agent for the treatment of dystonia. Epidemiologic studies on botulism suggest that the human nervous system is susceptible to five toxin serotypes (A, B, E, F and G) and resistant to two (C and D). In the past, these epidemiologic findings have been used as the basis for selecting serotypes that should be tested as therapeutic agents for dystonia. Epidemiologic data have been utilized because there are no studies of botulinum neurotoxin action on isolated human nerves. In the present study, electrophysiologic techniques were used to monitor toxin effects on neuromuscular transmission in surgically excised human pyramidalis muscles, ligand binding studies were done to detect and characterize toxin receptors in human nerve membrane preparations, and molecular biologic techniques were used to isolate and sequence a human gene that encodes a substrate for botulinum neurotoxin. The results demonstrated that stable resting membrane potentials (-61.5 mV; S.E.M. +/- 0.7) were maintained in individual fibers of pyramidalis muscle for up to 6 hr at 33 degrees C. The rate of spontaneous miniature endplate potentials was low in physiologic solution (0.14 sec(-1)) but increased in response to elevations in extracellular potassium concentration. In keeping with epidemiologic findings, botulinum toxin type A (10(-8) M) paralyzed transmission in human preparations (ca. 90 min). In contrast to epidemiologic findings, serotype C (10(-8) M) also paralyzed human tissues (ca. 65 min). Iodinated botulinum toxin displayed high-affinity binding to receptors in human nerve membrane preparations (serotype A high-affinity site: K(d) = 0.3 nM, B(max) = 0.78 pmol/mg protein; serotype C high-affinity site: K(d) = 1.96 nM, B(max) = 8.9 pmol/mg protein). In addition, the human nervous system was found to encode polypeptides that are substrates for botulinum neurotoxin types A (synaptosomal-associated protein of M(r) 25,000) and C (syntaxin 1A). These data have important implications bearing on: 1) the development and administration of vaccines against botulism and 2) the testing of toxin serotypes for the treatment of dystonia.

Botulinum Toxins↗
PubMed1996

Synaptic vesicle movements monitored by fluorescence recovery after photobleaching in nerve terminals stained with FM1-43.

We used the fluorescence recovery after photobleaching technique to monitor movements of synaptic vesicles in top views of living frog motor nerve terminals that had been prestained with the fluorescent dye FM1-43. In each experiment, a small portion of a single stained vesicle cluster was bleached with a laser and monitored subsequently for signs of recovery as neighboring, unbleached vesicles moved into the bleached region. In resting terminals, little or no recovery from photobleaching occurred. Repetitive nerve stimulation, which caused all fluorescent spots to grow dim as dye was released from exocytosing vesicles, did not promote recovery from photobleaching. Pretreatment with botulinum toxin (type A, C, or D) blocked exocytosis and destaining, but intense nerve stimulation still did not cause significant recovery in bleached regions. These results suggest that lateral movements of synaptic vesicles are restricted severely in both resting and stimulated nerve terminals. We tested for laser-induced photodamage in several ways. Bleached regions could be restained fully with FM1-43, and these restained regions could be destained fully by nerve stimulation. Partially bleached regions could be destained, although the rate of destaining was lower than normal. Brisk recovery from photobleaching occurred after treatment with okadaic acid, which disrupts synaptic vesicle clusters and causes vesicles to spread throughout the nerve terminal. These results suggest that vesicle translocation and recycling machinery was intact in photobleached regions.

Animals↗
PubMed1995

Amino acid sequence of a new type of toxic phospholipase A2 from the venom of the Australian tiger snake (Notechis scutatus scutatus).

Venom from the common tiger snake, Notechis scutatus scutatus, contains several toxic acidic proteins which promote hypotension and hemorrhage in mice. One of these toxins, HTe, has a phospholipase A2 (PLA2) amino acid sequence. It contains 125 amino acids rather than the 119/120 found in other N. s. scutatus PLA2s, because it also has the loop of residues (62-66) found in helix D of pancreatic PLA2s, the gamma-subunit of taipoxin, and the D-subunit of textilotoxin. High sequence identity is found between the first 57 and the last 25 amino acids of HTe and other N. s. scutatus PLA2s. In the central section containing the pancreatic loop and the beta-wing, sequence similarity with other N. s. scutatus PLA2s is low. The beta-wing amino acids are highly homologous to taipoxin-gamma. HTg, an isoform of HTe, has a sequence almost identical to that of HTe in the central section. Neuropharmacological and neurophysiological studies show that HTe blocks neuromuscular transmission, but it does not produce blockade by virtue of a selective action on nerve endings. Instead, the toxin acts both on nerve and on muscle. Unlike taipoxin-gamma and textilotoxin-D, HTe and HTg are not glycosylated and are not otherwise modified. HTe, HTg, and the other acidic proteins hydrolyze the synthetic PLA2 substrate, 3-octanoyloxy-4-nitrobenzoic acid, as well as L-alpha-phosphatidylcholine.

Amino Acid Sequence↗
PubMed1995

Limitations in the clinical prediction of intrapartum fetal asphyxia.

OBJECTIVE: Our purpose was to demonstrate the predictive value of clinical risk scoring and fetal assessment for intrapartum fetal asphyxia. STUDY DESIGN: Intrapartum fetal asphyxia was defined by an umbilical artery buffer base < 34 mmol/L. The predictive value of 20 antepartum and intrapartum risk factors was examined in 1909 consecutive pregnancies. The predictive value of clinical risk factors with periodic fetal assessment was examined in a second population of 100 consecutive pregnancies with biochemically determined intrapartum fetal asphyxia. RESULTS: The incidence of intrapartum was 2.3%. Two problems were apparent in these studies. A significant proportion of intrapartum fetal asphyxia occurred in pregnancies with no risk factors. The positive predictive value of clinical risk factors was low, 3%, resulting in a large number of false positives requiring clarification. CONCLUSION: Screening and fetal assessment methods must be improved to ensure the early recognition of intrapartum fetal asphyxia that may require intervention during labor to avoid morbidity and mortality.

Delivery, Obstetric↗
PubMed1995

Syndromes in twins.

There is a higher incidence of perinatal mortality and morbidity in twins than in singleton pregnancies. The main reason for this increase is the higher incidence of preterm delivery in twins. There are special conditions unique to twins that also contribute to this increased perinatal morbidity and mortality. These conditions include monoamniotic twins, congenital anomalies unique to twins, ie, conjoined twins and acardia, intrauterine fetal demise, and twin-to-twin transfusion syndrome. These conditions are the subject of this review. The prenatal determination of chorionicity is discussed first, because this assessment is key to the diagnosis and management of many of these conditions.

Amnion↗
PubMed1994

The role of transglutaminase in the mechanism of action of tetanus toxin.

Tetanus toxin is a zinc-dependent metalloendoprotease that cleaves synaptobrevin, a polypeptide found in the membranes of synaptic vesicles. This action is thought to account for toxin-induced blockade of transmitter release. However, Facchiano and Luini (Fachiano, F., and Luini, A. (1992) J. Biol Chem. 267, 13267-13271) have proposed that tetanus toxin can stimulate transglutaminase, and Facchiano et al. (Facchiano, F., Benfenati, F., Valtorta, F., and Luini, A. (1993) J. Biol Chem. 268, 4588-4591) have further proposed that the stimulated enzyme produces cross-linking of synapsin. These actions might also account for toxin-induced blockade of exocytosis. Therefore, a series of experiments were performed to evaluate the possibility that tetanus toxin exerts its effects via transglutaminase. The results indicated that clostridial neurotoxins were poor substrates for the cross-linking effects of transglutaminase, and transglutaminase was a poor substrate for the proteolytic actions of tetanus toxin. In addition, at concentrations relevant to blockade of exocytosis, clostridial neurotoxins did not act on intact cells to stimulate transglutaminase, nor did they act on the isolated enzyme to stimulate cross-linking of putrescine and dimethylcasein. When used as competitive inhibitors of endogenous transglutaminase substrates, glycine methyl ester and monodansylcadaverine did not block toxin action. Furthermore, concentrations of calcium that were too low to support transglutaminase activity did not prevent toxin action. The data suggest that stimulation of transglutaminase is not the principal mechanism by which tetanus toxin blocks exocytosis in nerve cells.

Amino Acid Sequence↗
PubMed1994

Diagnosis and treatment of structural fetal cardiac abnormality and dysrhythmia.

Although a great deal of controversy surrounds the concept of routine ultrasound screening, 70% of pregnant women in this country undergo ultrasound examination. Assessment of the fetal heart including a four-chamber view is recommended when ultrasound scans in the second and third trimester are performed. The accurate diagnosis of structural heart disease and cardiac dysrhythmias is now possible with advances in ultrasound and fetal echocardiography. Increased prenatal screening and genetic counseling have improved the management of these complicated pregnancies. It is hoped that the detection of significant congenital heart disease will continue to increase leading to further advances in medical and surgical treatment, improved patient care, and favorable perinatal outcomes.

Arrhythmias, Cardiac↗
PubMed1994

Inhibition of vacuolar adenosine triphosphatase antagonizes the effects of clostridial neurotoxins but not phospholipase A2 neurotoxins.

Bafilomycin A1, an inhibitor of vacuolar adenosine triphosphatase, was tested for its ability to antagonize botulinum neurotoxins (serotypes A-G), tetanus toxin and phospholipase A2 neurotoxins (notexin, beta-bungarotoxin, taipoxin and textilotoxin) on the mouse phrenic nerve-hemidiaphragm preparation. Bafilomycin itself produced concentration-dependent blockade of neuromuscular transmission without blocking nerve action potentials or muscle action potentials. This effect may have been due to inhibition of the proton pump that regulates acetylcholine transport into vesicles. At submaximal concentrations, bafilomycin was very effective in delaying the onset of paralysis due to all clostridial neurotoxins, but it had no protective effect against phospholipase A2 neurotoxins. Experiments were done to determine which of the three steps in clostridial neurotoxin action was antagonized by bafilomycin (e.g., binding, internalization and intracellular poisoning). Both pharmacological experiments and ligand-binding experiments showed that the drug did not block toxin binding to the plasma membrane. Similarly, pharmacological experiments on the time-dependent effects of bafilomycin showed that the drug did not antagonize the intracellular actions of toxins. The data indicated that bafilomycin acted at the intermediate step of internalization. This is in keeping with the facts that: 1) bafilomycin inhibits vacuolar adenosine triphosphatase, which in turn leads to inhibition of acidification in endosomes and 2) clostridial neurotoxins depend upon acidification of endosomes for translocation to the cytosol. The finding that bafilomycin antagonizes tetanus toxin may provide important clues for understanding how this toxin can act locally to produce flaccid paralysis. The finding that bafilomycin is a universal antagonist that protects against all clostridial neurotoxins may have important implications for developing therapeutic drugs.

Adenosine Triphosphatases↗
PubMed1993

Identification of the site at which phospholipase A2 neurotoxins localize to produce their neuromuscular blocking effects.

Experiments were conducted on mouse hemidiaphragm preparations using five phospholipase A2 neurotoxins of differing chain structures and antigenicities [notexin (one chain); crotoxin (two chains not covalently bound), beta-bungarotoxin (two chains covalently bound); taipoxin (three chains), and textilotoxin (five chains; one copy each of three chains and two copies of a fourth chain)]. Three clostridial neurotoxins (botulinum neurotoxin types A and B, and tetanus toxin) were used in comparison experiments. Phospholipase A2 neurotoxins produced concentration-dependent blockade of neuromuscular transmission. There was no obvious relationship between chain structure and potency, but there was an indication of a relationship between chain structure and binding. The binding of notexin was substantially reversible, the binding of crotoxin was slightly reversible, and the binding of beta-bungarotoxin, taipoxin and textilotoxin was poorly reversible. Experiments with neutralizing antibodies indicated that phospholipase A2 neurotoxins became associated with binding sites on or near the cell surface. This binding did not produce neuromuscular blockade. When exposed to physiological temperatures and nerve stimulation, bound toxin disappeared from accessibility to neutralizing antibody. This finding suggests that there was some form of molecular rearrangement. The two most likely possibilities are: (1) there was a change in the conformation of the toxin molecule, or (2) there was a change in the relationship between the toxin and the membrane. The molecular rearrangement step did not produce neuromuscular blockade. At a later time there was onset of paralysis; the amount of time necessary for onset of blockade was a function of toxin concentration. Phospholipase A2 neurotoxins were not antagonized by drugs that inhibit receptor-mediated endocytosis. In addition, phospholipase A2 neurotoxins did not display the pH-induced conformational changes that are typical of other endocytosed proteins, such as clostridial neurotoxins. However, phospholipase A2 neurotoxins were antagonized by strontium, and this antagonism was expressed against toxins that were free in solution and toxins that were bound to the cell surface. Limited antagonism was expressed after toxins had undergone molecular rearrangement, and no antagonism was expressed after toxin-induced neuromuscular blockade. The cumulative data suggest that phospholipase A2 neurotoxins are not internalized to produce their poisoning effects. These toxins appear to act on the plasma membrane, and this is the site at which they initiate the events that culminate in neuromuscular blockade.

Ammonium Chloride↗
PubMed1993

Chelation of zinc antagonizes the neuromuscular blocking properties of the seven serotypes of botulinum neurotoxin as well as tetanus toxin.

Botulinum neurotoxin types A, B (unactivated and activated), C, D, E, F and G, as well as tetanus toxin, paralyzed transmission in mouse phrenic nerve-hemidiaphragm preparations. Toxin-induced blockade of transmission was antagonized by chelators [e.g., ethylenediamine tetraacetic acid, tetrakis(2-pyridylmethyl)ethylenediamine or diethylene-triaminepentaacetic anhydride], but this effect was dependent on incubation conditions. Pretreatment of toxin with chelators failed to produce antagonism, but pretreatment of tissues did produce antagonism. Of the various chelators tested, tetrakis(2-pyridylmethyl)ethylenediamine produced the greatest effect. Antagonism of toxin-induced neuromuscular blockade could be partially reversed by washing chelators from tissues and could be fully reversed by adding an excess of zinc. The ability of chelators to antagonize clostridial neurotoxins was specific and did not extend to phospholipase A2 neurotoxins. Ligand-binding studies with radioiodinated toxin and brain membrane preparations showed that chelators did not antagonize toxicity by inhibiting toxin association with receptors. Similarly, pharmacological experiments with unlabeled toxin- and type-specific antibodies demonstrated that chelators did not act by blocking receptor-mediated internalization of toxin. The chelators appeared to exert their effects by antagonizing the intracellular actions of clostridial neurotoxins. Electrophysiological studies showed that chelators, at concentrations relevant to antagonism of botulinum neurotoxin and tetanus toxin, did not enhance transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The clinical diagnosis of asphyxia responsible for brain damage in the human fetus.

OBJECTIVE: Our objective was to review the clinical findings in infants who died in the perinatal period with brain damage attributable to asphyxia. STUDY DESIGN: The neuropathologic findings in 208 perinatal deaths have been reviewed. Thirty cases (22 fetal, eight newborn) had evidence of white matter or neuronal necrosis due to asphyxia. The clinical course of the pregnancy in 22 cases with brain damage attributable to fetal asphyxia were examined. RESULTS: The diagnosis of asphyxia was confounded by several factors: (1) asphyxia may occur at any time in the last half of pregnancy, (2) 50% of the antepartum asphyxia occurred when the pregnancy had no risk factors, (3) periodic fetal assessment in the complicated preterm pregnancies failed to identify the asphyxial episodes in the remaining cases of antepartum asphyxia, and (4) indicators of fetal asphyxia in the cases of intrapartum fetal asphyxia were obtained after the central nervous system injury had occurred. CONCLUSION: These findings highlight the difficulty in the diagnosis of fetal asphyxia at a stage that could permit intervention to prevent brain damage.

Adult↗