Biomedical subjects
D R Anderson
Publications and source records attributed to D R Anderson.
Sensitivity and specificity of a diagnostic test determined by repeated observations in the absence of an external standard.
Traditionally, the sensitivity and specificity of a new diagnostic test are derived from its application to two groups of individuals known to have or not to have met the criterion to be detected as judged by means of a "gold standard", some external time-honored test. In this study, a test with unknown accuracy parameters was used to detect an end-point criterion in an ongoing ophthalmological clinical trial. Since no external test method was available to assess the accuracy of this test, equations were derived relating the unknown sensitivity and specificity of the test to data frequencies based on replicate measurements. The solutions to these equations also provided estimates of the incidence rate of the criterion under investigation in the group tested, and of the predictive values of the test. The validity of this method of estimation is discussed, and applications to other situations are suggested.
Beta-adrenergic responsiveness of choroidal vasculature.
Using in vitro binding methods and autoradiographs, the authors showed that choroidal vessels specifically bind iodine 125 cyanopindolol, a nonselective blocker of beta-adrenergic receptors, in albino rabbits. In humans, the presence of beta-adrenergic receptors in choroidal vessels was confirmed by showing an increased choroidal vascular tone after systemic administration of timolol maleate, a nonselective beta-adrenergic blocker. Topically administered timolol maleate lowered the intraocular pressure but did not reach the choroidal receptors in sufficient quantity to produce a measurable effect on vascular tone.
Pseudo-loss of fixation in automated perimetry.
During automated perimetry with the Humphrey Visual Field Analyzer, field examinations are labeled unreliable whenever the reported rate of fixation loss is 20% or more. The reported rate of fixation loss results in part from times when the patient's gaze drifts from the fixation point during the examination, but also in part from technical artifacts such as faulty initial localization of the blind spot or false-positive responses by the patient. It was found that technical artifacts caused nearly half of the instances in which a field examination had a reported fixation loss rate of greater than 20%. It was also found that the perimetrist can prevent the artifacts, with the result that the frequency of field examinations labeled as having excessive fixation loss fell from 26% to 14%.
Skeletal muscle ventricles: update after 18 months in circulation.
Skeletal muscle ventricles (SMVs) have been constructed from canine latissimus dorsi muscle and connected to the aorta as aortic diastolic counterpulsators. Presently one dog remains alive and well with an SMV that has been functioning continuously in circulation for 18 months, without evidence of thromboembolic complications. SMVs are able to perform cardiac-type work with an output equal to that of the left ventricle at physiologic preloads, when tested with a mock circulation device in our laboratory. SMVs have been used for right-sided cardiac assist. In acute experiments these ventricles have functioned effectively, bypassing the right side of the heart for up to 8 h. Most recently we have tested SMVs using them chronically to pump blood in the right-sided circulation, and at the time of writing they have been shown to function effectively in this configuration for up to 18 days. SMVs may be used in the future as a method of treating patients with left- or right-sided heart failure.
Skeletal muscle ventricles: a promising treatment option for heart failure.
Our most recent work on cardiac assist with canine latissimus dorsi muscle in a skeletal muscle ventricle (SMV) configuration is reported here. One animal's SMV has been pumping blood effectively in the circulation for more than 16 months. To date there is no evidence of thromboembolism, and the dog has suffered no untoward effects. It has recently been shown, in a mock circulation study, that canine SMVs are capable of developing stroke work, at physiological preloads, much greater than that of the right ventricle and equivalent to that of the left ventricle. The improved ability of conditioned SMVs to perform work, independent of the circulation, during severe hypotension is also demonstrated. In the face of a 75% drop in left ventricular stroke work, the SMV stroke work dropped by only 50%. The continuing work on this subject suggests that a skeletal muscle ventricle may have the potential of becoming a viable alternative in the treatment of heart failure.
Cholinergic binding sites in pericytes isolated from retinal capillaries.
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Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and VX intoxication.
A pretreatment for organophosphorus (OP) anticholinesterase (e.g., soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts [mg/kg, im] tested were akineton [0.25], aprophen [8], trihexyphenidyl [2], atropine [16], azaprophen [5], benactyzine [1.25], cogentin [4], dextromethorphan [7.5], ethopropazine [12], kemadrin [1], memantine [5], promethazine [5], scopolamine [0.08] and vontrol [2]. PRGs were given 30 min before soman (60 micrograms/kg, sc; 2 LD50s) or other OP agents. Animals were then observed and graded for signs of intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs.
Effects of subacute pretreatment with carbamate together with acute adjunct pretreatment against nerve agent exposure.
Visual observations were made to compare the pretreatment benefits of subacute (75 micrograms/hr, sc) and acute (146 micrograms/kg, im, at 30 min) deliveries of physostigmine salicylate (Phy) against 2 or 5 LD50s (60 or 150 micrograms/kg, sc) of soman in guinea pigs; scopolamine, 80 micrograms/kg, im, was given routinely at 30 min. In a second set of studies, pretreatment with subacute carbamate [sc, Phy 36 micrograms/hr or pyridostigmine (Pyr), 50 micrograms/hr] and acute adjunct (im, scopolamine, 0.48 mg/kg, or trihexyphenidyl, 2 mg/kg) at 30 min, was used against soman (5 LD50s, sc) and VX (18.4 micrograms/kg, sc; 2 LD50s); atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) were given at 1 min post soman. In all studies, lethality, % convulsing, convulsive/subconvulsive score, and recovery time were noted. Subacute dosing for 7 days was done via 14-day osmotic minipumps (OMPs). Results of the first set of studies indicate that subacute and acute deliveries of Phy give essentially comparable protection against 2 or 5 LD50s of soman. The second set of studies show that against soman, the adjuncts scopolamine and trihexyphenidyl when compared, and the carbamates, Phy and Pyr when compared, gave similar protective benefits as indicated by all four monitored measures of toxicity. Phy with either adjunct provided excellent protection against VX induced mortality and convulsions. With both carbamates, trihexyphenidyl gave similar protective benefits against VX. Scopolamine, however, under the conditions used herein, failed to act beneficially with Pyr against VX.
Skeletal muscle as a myocardial substitute.
Although skeletal muscle currently offers a realistic means for providing functional support of the failing myocardium, more research is required to define the optimal mode of assist. The mechanism by which cardiomyoplasty augments cardiac function is unclear, although symptomatic improvement following the procedure is being increasingly reported. Skeletal muscle ventricles, on the other hand, have the potential to replace left ventricular function and have pumped effectively in the circulation for more than 1 year. With continued improvements in SMV design, the future for this mode of support is optimistic. The efficacy of some other forms of circulatory support using skeletal muscle remains to be elucidated.
Angiotensin II binding receptors in retinal and optic nerve head blood vessels. An autoradiographic approach.
Angiotensin II (AII) binding sites were identified in cross-sections of the cat retinal and optic nerve vasculatures. The authors used 3H-AII and 125I-saralasin, an agonist and a high-affinity antagonist of AII receptors, respectively, to generate light microscopy autoradiograms in resin-embedded tissues. With both radioligands the presence of AII binding sites was confirmed in retinal arterioles but not in the veins or capillaries of the retina. Additionally the presence of such binding sites in the capillaries of the optic nerve head was shown. These results support the hypothesis that microvascular tone and perhaps autoregulatory responses of optic nerve capillaries might be influenced by vasoactive substances, such as AII, either leaking from the choroid or locally synthetized.
Autogenously lined skeletal muscle ventricles in circulation. Up to nine months' experience.
Skeletal muscle ventricles were constructed in fifteen dogs. After a delay period of 4 weeks the skeletal muscle ventricles were connected to the descending thoracic aorta with a polytetrafluoroethylene bifurcation graft (Gore-Tex bifurcation graft, W.L. Gore & Associates, Inc., Elkton, Md.). The aorta was ligated between the two limbs of the graft so that there was obligatory blood flow through the skeletal muscle ventricle. Nine skeletal muscle ventricles were lined with autogenously derived tissue, either pleura or pericardium, whereas six had no specific lining other than an induced fibrous reaction. The skeletal muscle ventricles were activated to contract during cardiac diastole. Aortic diastolic counterpulsation was achieved in all dogs, with ten surviving from 1 week to beyond 9 months. Thrombus eventually developed in all but three of the skeletal muscle ventricles, but no dog had clinical evidence of thromboemboli. The three thrombus-free skeletal muscle ventricles were lined with pleura, including the animal surviving beyond 9 months. These results indicate that canine skeletal muscle can provide aortic diastolic counterpulsation for 9 months without clinically apparent thromboembolic complications.
Evaluation of several oximes as reactivators of unaged soman-inhibited whole blood acetylcholinesterase in rabbits.
The antidotal benefit of oximes against organophosphorus (OP) anticholinesterase intoxication is thought to be due to reactivation of the OP-inhibited acetylcholinesterase (AChE). This study was conducted to determine whether the antidotal efficacy against soman by the oximes 2-hydroxyiminomethyl-3-methyl-1-[2-(3-methyl-3-nitrobutyl oxymethyl)]-imidazolium Cl (ICD 467) and 1,1'-methylenebis[4-(hydroxyiminomethyl) pyridinium] di-Cl (MMB-4) resulted, in part, from reactivation of the inhibited AChE. These oximes were tested in parallel with pralidoxime Cl (2-PAM) and 1-(2-hydroxyiminomethyl-1-pyridinio-3-(4-carbamoyl-1-pyridinio+ ++)-2-oxapropane di-Cl (HI-6). Rabbits were atropinized (8 mg/kg, i.m.) and intoxicated with soman (13 micrograms/kg, i.v.; 1.2 x LD50) 5 min later. Three minutes after soman, animals were treated with oxime (50, 100 or 150 mumol/kg, i.m.). Whole blood was collected from a catheter in the central artery of the ear just before soman, at 2 min after soman and at 2, 5, 10, 15, 30, and 60 min after oxime or vehicle for determination of AChE activity. Shortly thereafter, animals were anesthetized and exsanguinated with immediate flushing using heparinized saline. AChE activity was also determined on the cortex, medulla-pons and diaphragm to assess central and peripheral reactivation. Treatment with HI-6 or MMB-4 (50 mumol/kg, i.m.) resulted in significant (P less than 0.05) reactivation of soman-inhibited whole blood AChE and diaphragm cholinesterase (ChE), but not brain AChE. In contrast, 2-PAM was completely ineffective in reactivating soman-inhibited AChE. HI-6 was significantly better than MMB-4 in reactivating blood AChE; they were essentially equal against soman-inhibited diaphragm ChE. Three animals exposed to soman and treated with ICD 467 died within 15 min. When animals not exposed to soman were treated with ICD 467 (25 mumol/kg, i.m.), whole blood AChE activity was depressed by 60% within 5-10 min after treatment. Furthermore, ICD 467 failed to reactivate significantly unaged soman-inhibited erythrocyte AChE, in vitro. These observations indicate that ICD 467 would be contraindicated as a therapy for anti-ChE intoxication and that the efficacy of HI-6 or MMB-4 can be explained, in part, by reactivation of soman-inhibited AChE.
The effect of iridotomy on iris contour.
With a recently developed technique for quantifying the geometry of the anterior chamber in optical cross section (slit-lamp photography using the Scheimpflug principle and computer correction for the optical effects of the cornea), we studied the iris contour before and after iridotomy in six patients with narrow anterior chamber angles and angle-closure glaucoma. Before iridotomy, the iris contour was convex anteriorly in all meridians. After iridotomy, the anterior lens surface position did not change perceptibly. The iris at the pupil margin settled backward onto the lens surface, no longer held forward by the narrow stream of aqueous passing from the posterior chamber to the anterior chamber. Next to the pupil there was often a perceptible mound, presumably representing the iris sphincter. From the point of support by the lens to the root of the iris, the contour of the iris surface was a straight line, except for the surface irregularities. The deepening of the anterior chamber at each point was the difference between the convex contour before iridotomy and the straight line after iridotomy.
Laser and unsutured sclerotomy in nanophthalmos.
Among 30 eyes with nanophthalmos, 21 had angle-closure glaucoma and two had open-angle glaucoma associated with pseudoexfoliation of the lens capsule. Laser iridotomies, sometimes combined with laser iridoplasty, were sufficient to control, or to allow medical control of, the glaucoma in 15 of 18 eyes. Four eyes with uveal effusion underwent an unsutured sclerotomy or sclerectomy, and all had resolution of the choroidal detachment within two weeks. Cataract extraction improved the vision in seven of nine eyes. Previous or simultaneous sclerotomy or sclerectomy was performed on all nine eyes that underwent cataract extraction and in two eyes at the time of glaucoma surgery; no eye had postoperative uveal effusion or other major complications. Laser iridotomy and iridoplasty, sometimes with supplemental medical therapy, are often sufficient in the treatment of angle-closure glaucoma in nanophthalmos and are safer than surgery. Nanophthalmic uveal effusion can be prevented or treated with an unsutured sclerotomy or sclerectomy.
Ultrastructural changes in knee ligaments following immobilization.
Anterior cruciate (ACL) and medial collateral (MCL) ligaments from control and immobilized rabbit knee joints were examined using transmission electron microscopy. The fibroblasts of these two tissues were distinct in control ligaments, but these differences in fibroblast morphology were less obvious after immobilization. The most drastic changes took place in the ACL; the ACL fibroblasts from control ligaments were ovoid-shaped, while after immobilization they were spindle-shaped with extensive cytoplasmic extensions. These cellular changes corroborate previously demonstrated changes in the mechanical properties of these ligaments seen following immobilization, and are consistent with biochemical studies.
Side-effects of antithrombotic therapy.
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