Lyme disease study.
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Clinical Protocols↗
Biomedical subjects
D R Anderson
Publications and source records attributed to D R Anderson.
Accuracy of clinical assessment of deep-vein thrombosis.
The clinical diagnosis of deep-vein thrombosis is generally thought to be unreliable. From experience, we hypothesised that this widely held view might be incorrect. We developed a clinical model and prospectively tested its ability in three tertiary care centres to stratify symptomatic outpatients with suspected deep-vein thrombosis into groups with high, moderate, or low probability groups of deep-vein thrombosis. We evaluated our clinical model in combination with venous ultrasonography to determine the potential for an improved and simplified diagnostic approach in patients with suspected deep-vein thrombosis. All patients were clinically assessed to determine the probability for deep-vein thrombosis before they had ultrasonography and venography. All tests were performed and interpreted by independent observers. In 529 patients, the clinical model predicted prevalence of deep-vein thrombosis in the three categories: 85% in the high pretest probability category, 33% in the moderate, and 5% in the low category. There was no statistical difference in the performance of the model in the three centres. The model demonstrated excellent interobserver reliability (Kappa = 0.85). There were important differences with ultrasonography between the high and low pretest probability groups for both positive predictive values (100% (95% CI, 94-100%) vs (63% [35-85%], respectively). Thus, use of the clinical model combined with ultrasonography would decrease the number of false positive and negative diagnosis if venography were done when the ultrasound result and pretest probability were discordant. The diagnostic process could be simplified by excluding those patients with low pretest probability and normal ultrasound results from serial testing.
Decision Trees↗
Thromboembolism after major trauma.
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Humans↗
Potential use of the intercostal artery as an in situ graft: a cadaveric study.
The third to eighth intercostal arteries (ICAs) were bilaterally dissected in 10 cadavers to assess their length and possible routes to coronary arteries if used as in situ grafts. The mean lengths for the intercostal arteries harvested were 27.0 +/- 2.9 cm on the left and 27.4 +/- 3.2 cm on the right. The shortest anatomic route to the coronary arteries of the in situ ICAs harvested was medial to the lung and either superior to or inferior to the hilum. By using either the superior or inferior routes in situ ICAs were long enough to reach the major coronary artery territories in all cadavers. The most suitable ICAs for grafting the coronary arteries and the shortest routes were as follows: left anterior descending--left fifth ICA by inferior route; circumflex coronary artery-left fifth ICA by inferior route; and right coronary artery-right seventh ICA by inferior route. We conclude that it is anatomically feasible to use the intercostal artery as an in situ graft in coronary artery operation.
Aged↗
Three examples of Rh haemolytic disease of the newborn with a negative direct antiglobulin test.
Typically the serological diagnosis of alloimmune haemolytic disease of the newborn (HDN) includes a positive direct antiglobulin test on the infant's red cells, and the presence of an IgG red cell alloantibody in both maternal and cord sera. HDN with a negative direct antiglobulin test has been reported with anti-A and anti-B, but not with other red-cell alloantibodies. In this report we describe four examples of HDN in infants whose red cells had a negative direct antiglobulin test. The first case was diagnosed retrospectively when the infant was admitted to hospital aged 3 weeks with severe anaemia and cardiac failure, and subsequently died. Maternal and infant sera were both shown to contain anti-C: however, the direct antiglobulin test on the infant's red cells was negative. Approximately 1 year later the mother of this infant gave birth to triplets: soon after birth one of the triplets required an exchange transfusion, one had hyperbilirubinaemia, and the third was unaffected. Anti-C and anti-e were detectable in the maternal serum at this time. The most probable Rh genotypes of the two affected infants were R1R2 (CDe/cDE), while the Rh genotype of the unaffected infant was R2R2 (cDE/cDE). Anti-c was implicated as causing HDN in a fourth infant (from a different family) who was a hydropic stillborn. The direct antiglobulin test on fetal blood was negative and other causes of non-immune hydrops were excluded. These four infants provide evidence that the direct antiglobulin test may be negative in some severely affected and even fatal cases of HDN.
Coombs Test↗
GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons.
Evidence from electrophysiological studies has suggested an inhibitory interaction between GABAergic neurons in substantia nigra pars reticulata and dopaminergic neurons in pars compacta. However, that this inhibitory interaction is due to a projection from pars reticulata to pars compacta has never been demonstrated directly, nor has the GABAergic neuron that mediates the interaction been identified either electrophysiologically or anatomically. To more closely examine interactions between substantia nigra pars reticulata GABA neurons and dopaminergic neurons, single unit extracellular recordings were obtained from antidromically identified nigrostriatal neurons and their response to antidromic activation of nigral GABAergic projection neurons observed. Stimulation of superior colliculus or thalamus produced a short latency inhibition of dopaminergic neurons. This inhibition was blocked by local application of bicuculline but not 2-hydroxysaclofen. Bicuculline caused most dopaminergic neurons to fire in a bursty mode, whereas saclofen caused most dopaminergic neurons to fire in a pacemaker-like mode. The thalamic-evoked inhibition was not affected by kainate lesions of the globus pallidus, but these lesions produced effects on firing pattern identical to those produced by saclofen. These data demonstrate a short latency inhibition of nigral dopaminergic neurons mediated by GABAA receptors that arises from the axon collaterals of pars reticulata projection neurons. We propose a model in which the firing pattern of nigral dopaminergic neurons in vivo is modulated differentially by disinhibition of GABAA inputs arising from pars reticulata projection neuron axon collaterals and disinhibition of pallidonigral GABAergic inputs mediated by GABAB receptors.
Animals↗
Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
Murine monoclonal antibody 2B8 specifically recognizes the CD20 phosphoprotein expressed on the surface of normal B lymphocytes and B-cell lymphomas. The light- and heavy-chain variable regions of 2B8 were cloned, after amplification by the polymerase chain reaction, into a cDNA expression vector that contained human IgG1 heavy chain and human kappa-light chain constant regions. High-level expression of chimeric-2B8 antibody (C2B8) was obtained in Chinese hamster ovary cells. Purified C2B8 exhibited antigen binding affinity and human-tissue reactivity similar to the native murine antibody. In vitro studies showed the ability of C2B8 to bind human C1q, mediate complement-dependent cell lysis of human B-lymphoid cell lines, and lyse human target cells through antibody-dependent cellular cytotoxicity. Infusion of macaque cynomolgus monkeys with doses ranging from 1.6 mg/kg to 6.4 mg/kg resulted in greater than 98% depletion of peripheral blood (PB) B cells and 40% to 70% depletion of lymph node B cells. Recovery of PB B cells usually started at 2 weeks after treatment and required 60 to greater than 90 days to reach normal levels. As much as 95% depletion of B cells in peripheral lymph nodes and bone marrow was observed following weekly injections of 16.8 mg/kg antibody. No toxicity was observed in any of the animals. These results offer the possibility of using an "immunologically active" chimeric anti-CD20 antibody as an alternative approach in the treatment of B-cell lymphoma.
Amino Acid Sequence↗
Erythrocyte and plasma cholinesterase activity in male and female rhesus monkeys before and after exposure to sarin.
The rhesus monkey (Macaca mulatta) has a menstrual cycle similar to the human. Differences in hormone levels have been demonstrated between the sexes and in females during the menstrual cycle but these differences in terms of organophosphorus toxicity have not been explored. Plasma cholinesterase (ChE/BuChE) and erythrocyte (RBC) acetylcholinesterase (AChE) activity were measured before and after exposure to the organophosphorus compound sarin (11 micrograms/kg, i.v.; 0.75 LD50) in six male and six female rhesus monkeys. After baseline measurements were obtained, sarin was administered to atropinized monkeys to determine in vivo differences between the sexes in their response to sarin. With the baseline values, the intraanimal and intragroup BuChE/AChE variations were found to be minimal. Following sarin intoxication and 2-PAM treatment no significant differences were seen between the sexes in the rate of reactivation of BuChE or AChE by 2-PAM. The rate of aging of sarin phosphonylated RBC AChE between the sexes was also similar. De novo regeneration of RBC AChE and plasma BuChE after sarin intoxication was different between the male and female monkeys. The female plasma BuChE recovery rate was 48% slower than the male recovery rate, while the early (first 63 days) RBC AChE recovery rate was 24.5% faster in the females. In conclusion, there probably are not any clinically significant differences between male and female rhesus monkeys acutely intoxicated with sarin. However, on subsequent exposure clinical differences may be observed due to substantial differences in the rate of de novo synthesis of both plasma BuChE and RBC AChE.
Acetylcholinesterase↗
Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis.
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Animals↗
Thrombolytic therapy for the treatment of acute pulmonary embolism.
OBJECTIVES: To determine whether thrombolytic therapy reduces the rate of death or complications in patients with acute pulmonary embolism and whether a particular thrombolytic regimen is more effective than others. DATA SOURCES: The key words "fibrinolytic agents," "plasminogen activators," "streptokinase," "urokinase" and "pulmonary embolism" were used to search MEDLINE for relevant articles in English; the bibliographies of these articles were reviewed for additional publications. STUDY SELECTION: Articles were included if they were of a randomized controlled design; 10 such articles were found. DATA EXTRACTION: Ten trials were appraised with the use of the following methodologic criteria: a clear description of the study population; use of objective criteria to diagnose pulmonary embolism and to assess outcomes; use of clinically relevant outcomes; and blinded outcome assessments. RESULTS: In the nine trials that met the methodologic criteria thrombolytic therapy led to a more rapid resolution of the radiographic and hemodynamic abnormalities associated with acute pulmonary embolism than did anticoagulant therapy alone, although these benefits were short-lived. No difference was detected in the death rate or the resolution of symptoms between patients receiving thrombolytic therapy and those receiving anticoagulant therapy alone. In addition, bleeding complications were more frequent and serious in patients who received lytic therapy, although these events were related to the use of invasive procedures. CONCLUSION: There is a lack of evidence that thrombolytic therapy improves clinically relevant outcomes of patients with acute pulmonary embolism. This may be a reflection of the small sample size of the clinical trials. Further research is required to define the role of thrombolytic therapy in the management of patients with acute pulmonary embolism.
Evaluation Studies as Topic↗
Immune-related disease and normal-tension glaucoma. A case-control study.
We reviewed the charts of 67 patients with the diagnosis of normal-tension glaucoma listed in the Bascom Palmer Eye Institute computer database. These patients were matched with respect to age, race, and sex with an equal number of patients having ocular hypertension. All medical diagnoses in the charts for both groups were tabulated and classified as either immune-related or non-immune-related. Twenty (30%) patients with normal-tension glaucoma had one or more immune-related disease(s) compared with five (8%) patients in the comparison group (P = .00134, McNemar statistic with continuity correction).
Aged↗
Bilateral striopallidodentate calcinosis: cerebrospinal fluid, imaging, and electrophysiological studies.
We report the genetic, clinical, electrophysiological, and imaging studies in a family with bilateral striopallidodentate calcinosis (Fahr's disease). The intracerebral calcium deposits occurred before onset of the symptoms in the third decade of life. Progressive neurological deterioration occurred in the fifth decade of life in the proband. Cerebrospinal fluid homocarnosine, a central nervous system-specific peptide, was increased twofold in patients with autosomal dominant bilateral stripallidodentate calcinosis; in sporadic cases, there was no detectable homocarnosine and a decreased level of histidine. With advancing age, the amount of calcification increases, but it has not been determined if a critical amount must be reached before symptoms occur. Computerized tomography is superior to magnetic resonance imaging for radiological diagnosis. Despite diffuse striatal calcification, striatal 6-[18F]fluoro-L-dopa uptake did not reveal any difference between patients and control subjects, from which we infer persisting integrity of the nigrostriatal dopaminergic pathway.
Adult↗
Healing of the medial collateral ligament following a triad injury: a biomechanical and histological study of the knee in rabbits.
The effect of a partial medial meniscectomy and anterior cruciate ligament (ACL) transection on medial collateral ligament (MCL) healing was studied in skeletally mature rabbits. Two groups of animals, group I (isolated MCL rupture) and group II (MCL rupture with ACL transection and partial medial meniscectomy), were examined. At 6 and 12 weeks postoperatively, histological examination of the healing MCL and biomechanical evaluation of the varus-valgus (V-V) knee rotation and tensile properties of the femur-MCL-tibia complex (FMTC) were performed. Group II animals experienced substantial joint degeneration by 6 weeks. Progressive osteophyte formation was observed adjacent to the MCL insertions along with proximal migration of the MCL tibial insertion between 6 and 12 weeks. Histologic examination of the healing MCL substance from both groups showed disorganized collagen, inflammation, and fibroblast proliferation that decreased over time. For group II knees, the V-V knee rotation was found to be significantly elevated (4.7 to 5.2 times the contralateral control), and did not decrease with time. In contrast, the V-V knee rotations of the group I specimens were 1.8 times greater than control immediately following injury, and approached control values by 12 weeks. Tensile testing of the FMTCs revealed that the ultimate load increased with time for both groups, but group I had significantly higher values than group II. The linear stiffness in group I was not different than that group II and did not increase with time. For the mechanical (material) properties of the healed MCL substance, the modulus of the healing tissue for group II was only 40% that of group I. The structural properties of the FMTC and the mechanical properties of the MCL substance from both groups at 6 and 12 weeks were significantly different from the contralateral controls. We further demonstrated that immediately after ACL reconstruction, the V-V rotation of group II knees could be restored to group I levels. Recent clinical studies of MCL healing following isolated complete ligament tears have suggested that nonoperative management without immobilization leads to excellent treatment outcome. However, in more severe injuries involving additional tissues, poor quality of the healed ligament tissue and articular degeneration are observed. Our results demonstrate the deleterious effects of an untreated triad injury on the healing of the MCL substance and its insertions. Examination of the MCL substance suggests that a much larger healing mass is formed following a triad injury, which partially compensates for inferior ligament mechanical properties.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents.
This study concerned the effect of pyridostigmine pretreatment on (a) the antidotal efficacy of atropine and 2-PAM in sarin, tabun, and VX poisoning in mice and guinea pigs and on (b) the oxime-induced reactivation of VX-inhibited whole blood acetylcholinesterase (AChE) of guinea pigs. One hour prior to organophosphate (OP) challenge with sarin, tabun, or VX, animals were given oral doses of pyridostigmine to induce approximately 30 and 60% inhibition of whole blood AChE; controls received vehicle. Mice were challenged im and guinea pigs sc with the OP compounds. Treatment with atropine (11.2 mg/kg to mice; 32 mg/kg to guinea pigs) plus 2-PAM (25 mg/kg) was given im at 10 sec postchallenge in mice and 1 min postchallenge in guinea pigs. In the reactivation experiments, pyridostigmine or saline was given im to guinea pigs 30 min prior to VX (8.24 micrograms/kg, sc), atropine (16 mg/kg) was given im at 1 min, and 2-PAM (25 mg/kg) at 16 min postchallenge. Pyridostigmine significantly enhanced the efficacy of atropine and 2-PAM against tabun in both species. In contrast, pyridostigmine reduced or did not increase the efficacy of atropine and 2-PAM against sarin or VX in both species. Recovery of VX-inhibited AChE by 2-PAM was decreased significantly in pyridostigmine pretreated animals. The results suggest that pyridostigmine pretreatment may adversely effect the efficacy of atropine and 2-PAM as antidotes for VX and sarin intoxication.
Acetylcholinesterase↗
Idiotype network responses to murine immunoglobulin G3 anti-carbohydrate antibodies.
Two murine monoclonal antibodies, 8A6 and 8C2, were generated against the carbohydrate moiety of tumor-associated disialoganglioside. Both of the antibodies were of the immunoglobulin G3 (IgG3), K isotype subclass. One of these antibodies (8A6) was used as a network immunogen for the generation of anti-idiotype antibodies. Two AB2 anti-idiotype antibodies were identified. One AB2 (12E5) was subsequently shown to recognize a linear epitope of the 8A6 kappa light chain. The second AB2 (9H8), recognizes a conformational epitope which is dependent on the maintenance of the tertiary structure of the idiotype. Both anti-idiotypes were injected into (syngeneic) mice and (xenogeneic) rabbits to evaluate their effectiveness as "network" antigens in promoting AB3 and anti-carbohydrate AB1' responses. AB3 populations from both syngeneic and xenogeneic hosts were found to be idiotype-specific, yet were unable to produce a measurable subpopulation of anti-tumor (AB1'). These studies suggest that IgG3 isotypes may not be suitable idiotype templates for the mimicry of carbohydrate epitopes.
Animals↗
Screw fixation in the human sacrum. An in vitro study of the biomechanics of fixation.
A load-to-failure test was used to study the biomechanical properties of sacral screw fixation in human cadaveric specimens. The goals of this study were 1) to determine the effects of the two commonly chosen sacral screw orientations of fixation characteristics; 2) to determine the effects of selected screw-instrumentation linkages on the biomechanics of sacral screw fixation; 3) to correlate the biomechanical properties with a noninvasive assessment of sacral bone density; and 4) to correlate the torque during screw insertion with these biomechanical properties. The bone density of each specimen was measured with quantitative computed tomography. A screw was inserted from the dorsal surface either anteromedially or anterolaterally into the body of S1, and the torque needed to insert each screw was measured. The screw head was attached to a constrained or semiconstrained loading linkage. Force was applied to the screw in an inferior direction until the maximum load was achieved. The maximum load, screw translation, rotation at maximum load, and initial compliance of the bone-screw interface were determined. It was found that the anteromedial screw orientation, combined with a rigidly constrained loading linkage, resulted in the greatest maximum load to failure, the least screw rotation, and the least initial compliance of the four groups studied. The maximum load and the initial stiffness of bone-screw fixation increased significantly with bone density. Torque measurements correlated significantly with maximum load to failure, initial interface stiffness, and bone density. It was therefore concluded that bone density and torque measurements can be useful in assessing sacral screw fixation.
Aged↗
Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy.
Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.
Adult↗
Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning.
The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepam, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. All compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (mumol/kg) values and peak effect times were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepam, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock [MES] and subcutaneous pentylenetetrazol [scMET]). The results suggest that at anticonvulsant doses against nerve agents, all the benzodiazepines and phenobarbital have the potential to cause a performance decrement, whereas candidate anticonvulsants of the non-benzodiazepine or non-barbiturate type would not be expected to demonstrate this effect on motor performance. It is concluded that compounds such as acetazolamide, amitriptyline and scopolamine offer alternatives to the highly decrementing benzodiazepines and phenobarbital and should be further tested as anticonvulsant candidates against nerve agent intoxication.
Acetazolamide↗