Biomedical subjects
Publications and source records attributed to J Engel.
We believe that ORTHOX is a practical solution for the evaluation of x-rays giving a fast and accurate reading, that can be performed by every physician, even if his orthopaedic experience is still limited.
This chapter describes tomographic and autoradiographic studies of human and animal seizure syndromes employing Sokoloff's deoxyglucose method. The method's rationale rests on two principal facts: that adult brains normally utilize glucose almost exclusively as their exogenous energy source, and that deoxyglucose, a glucose analog, accumulates in brain cells in proportion to their activity level. Thus, computed tomography or contact autoradiography allows visualization and indirect measurement of changes in the activity of different brain structures under specified conditions, such as between, during, or immediately following seizures. In humans, partial seizures have been the most extensively studied, with 18F-fluorodeoxyglucose and positron emission tomography. Interictally, the brains of patients with partial seizures are characterized by hypometabolism that is particularly severe in the vicinity of seizure foci. In many cases, these focal hypometabolic zones become hypermetabolic ictally. Other brain areas may also become hypermetabolic ictally, or they may instead become hypometabolic. Often the physical extent of interictal hypometabolic zones is substantially greater than the extent of overt pathology. This indicates that hypometabolism can result from subtle, presently undescribed, structural or functional derangements, as well as from frank neuronal loss. A variety of animal seizure "models" have also been studied, with 14C-2-deoxyglucose and contact autoradiography. Each model has produced a unique deoxyglucose and contact autoradiography. Each model has produced a unique deoxyglucose utilization pattern, but thus far none that closely resembles any of the human seizure patterns. This probably reflects true differences between the mechanisms mediating different types of animal seizures and those mediating human seizures. Although in widespread use for only a few years, the Sokoloff method has already demonstrated its ability to distinguish among a variety of seizure types in both humans and animals, and to correctly identify those structures most involved in focal seizures. Thus, the method can be of great aid in narrowing the search for seizure-mediating mechanisms.
Studies on structure-activity relationships of organometallic anticancer drugs are reviewed. Three methods for the development of new structures are described. Drug targeting: platinum complexes with oestrophilic ligands were synthesized, and the endocrine and cytostatic effects are discussed. Quantitative structure-activity relationship determination is presented as a rational method for the design of active compounds. The molecular modelling technique is used for the analysis of molecular properties.
A detailed three-dimensional model of the collagenous part of C1q was derived by model building and computer-aided energy refinement calculations. The proposed structure is based on the collagen-like (-Gly-Xaa-Yaa-) repeating sequence of 78 to 81 residues in the N-terminal regions of the constituent A, B and C chains, on the mode of disulphide linkage between the 18 chains of C1q, and on its electron microscopically derived gross structure. It is demonstrated that the interruptions of the repeating sequence about half-way along the length of the collagenous regions (Gly36-Ile37-Arg38-Thr39 in the A chain and Ala36-Ile37-Hy138 in the C chain) do not lead to a disruption of the triple helical conformation but rather to a bend of about 60 degrees in an otherwise continuous triple helix. These features are consistent with a flexibility comparable with that of regular triple helices and with the observed low proteolytic susceptibility of the kink region. The azimuthal orientation of the kink is defined approximately by ArgA38 being located in the cap of the knee. Because of this extra residue between two glycine residues, a bad contact that would arise between the methyl group of AlaC36 and the peptide carbonyl of IleA37 in a straight triple helix is relaxed. The model features also a cluster of hydrophobic contacts between large hydrophobic side-chains in the interaction edges between the six collagen triple helices aligned with their about 10 nm long N-terminal regions in the fibril-like endpiece of C1q. The azimuthal orientations of the triple helices were derived by energy calculations of side-chain interactions previously applied to fibre-forming collagens. Independently, the same orientations and interaction edges were derived from the azimuthal orientation of the kink and the electron microscopically observed orientations of the triple helical arms that emerge from the endpiece, and which carry the C-terminal globular binding domains. The structural model has a number of implications for the assembly of the first component of complement from C1q and the zymogen complex C1r2C1s2 and possible mechanisms of its activation.
By attaching native collagen and C1q to Sepharose, it was possible to test the binding of fibronectin (Fn) to the native and heat-denatured forms of these proteins without complications due to aggregation, precipitation, or fibril formation. Binding to the native proteins occurred only at low (sub-physiological) ionic strength whereas binding to the denatured proteins occurred even in 1 M NaCl. Thus both of these proteins possess one or more strong sites which are masked in the native state and become exposed during thermal denaturation. Fn did not bind to albumin-Sepharose or IgG-Sepharose either before or after heat-denaturation. C1q bound readily to native IgG-Sepharose but did not mediate the binding of Fn. Nor did Fn inhibit the reconstitution of C1 on antibody-coated erythrocytes. The fluorescence polarization of fluorescein-labeled collagen in 1 M NaCl displayed a downward transition at 38-40 degrees C consistent with unfolding of the triple helix. In the presence of Fn, the same material displayed an upward transition at slightly lower temperature suggesting that gross unfolding is not required to expose the strong binding site(s).
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Four patients with primary generalized or true petit mal epilepsy were studied with positron emission tomography using [18F]fluorodeoxyglucose (FDG). FDG studies were carried out during 10 minutes of hyperventilation before and again after medical control of spontaneous absences. Before seizures were controlled all 4 patients demonstrated frequent bilaterally synchronous three-per-second spike-and-wave discharges associated with altered consciousness. After spontaneous seizures were controlled, hyperventilation produced only electroencephalographic slowing without clinical symptoms in 3; the fourth patient had absences less frequently. Patterns of local cerebral metabolic rate for glucose (CMRGlc) were normal and identical for ictal and interictal scans; there was, however, a 2.5- to 3.5-fold diffuse ictal increase in global CMRGlc evident when ictal studies were compared with hyperventilation control studies in which no seizures occurred. The CMRGlc was similar in the two scans obtained from the patient who had absences during both studies. No anatomical substrate of petit mal epilepsy was identified. The CMRGlc in these patients during petit mal absences was higher than that recorded in other patients during partial or generalized convulsive seizures. This difference may reflect the fact that petit mal absences are not associated with postictal depression.
A prospective study was performed to evaluate the usefulness of ear, anterior temporal, and nasopharyngeal electrodes for recognizing temporal lobe epileptic electroencephalographic (EEG) foci. One hundred and three EEGs were performed on patients suspected of having epilepsy who had a previous normal record. Nasopharyngeal electrodes were simultaneously compared with ear and anterior temporal electrodes to determine their relative abilities to detect pathological epileptiform transients from the temporal region. Epileptic discharges were detected in 22% of the recordings. Pathological discharges seen in nasopharyngeal electrode derivations invariably were seen in ear and anterior temporal electrode derivations using carefully designed montages, and EEG diagnosis was not altered by use of nasopharyngeal electrodes. We conclude that EEG recording with ear and anterior temporal electrodes is sufficient to detect pathological temporal epileptiform transients, and that the use of nasopharyngeal electrodes as a routine procedure offers no added benefit.
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Three new laminin fragments, E8, E9 and 25K with mol. wt. 50 000-280 000, were prepared from a limited elastase digest of laminin and from tissue extracts. They were similar with respect to their rod-like structure, a high alpha-helix content, the assembly from two chain segments and immunological cross-reactivity. Two of the fragments (E8 and E9) possess in addition globular domains which lack alpha-helices. Chemical, immunological and physical data together with sequence analysis strongly indicate that the alpha-helical segments are assembled in coiled-coil structures which are located in the rod of the long arm of laminin. These data give new insights into the overall structure of the protein.
Weanling rats were treated with diazepam, apomorphine, and haloperidol to study the influence of the dopamine (DA) system on the audiogenic immobility reaction and open field locomotory behavior. Treatment with diazepam (0.025, 0.05, and 0.1 mg/kg) caused a dose-dependent shortening of the duration of the immobility response. Treatment with apomorphine (0.125, 0.25, and 0.50 mg/kg) shortened both the immobility reaction and the latency to leave the spot where the animal was first placed in the open field (latency for first crossing). Locomotor activity increased in a dose-dependent fashion. Both grooming and rearing showed biphasic dose response curves, with a maximum occurring at the 0.125 mg/dose for grooming and at the 0.25 mg/dose for rearing. Haloperidol (0.06 mg/kg) exerted opposite effects to those of apomorphine, but also produced increased running during the auditory stimulation (flight distance). Using the immobility reaction as an expression of fear, we concluded that activation of the DA system decreases while inhibition of the DA system increases fear. It was hypothesized that the DA system exerts an inhibitory function in the expression of fear.
A thirty-seven-year-old male with Osteoid Osteoma of the proximal ulna is described. He had suffered from pain in his elbow for two and a half years prior to diagnosis. Computer Tomography demonstrated and localised the nidus which was surgically removed.
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Female rats were given 16% ethanol solution as the sole liquid during the entire period of gestation. At birth the offspring was removed and reared by foster dams consuming normal tap water. At adult age the female offspring showed deficiencies in their maternal behaviour; they built nests of poor quality and they displayed prolonged times for retrieving pups placed outside the nest. In the whole brains of the prenatally ethanol-exposed females a decreased serotonin synthesis was observed. The offspring of the prenatally ethanol exposed mothers did not show any signs of disturbances in physical or behavioural development.
Female rats were given 16% ethanol solution as the sole liquid during the entire period of gestation. At birth the offspring was removed and reared by foster dams consuming normal tap water. The development of sensory motor behaviour and emotional reactions was delayed by 1-2 days in the prenatally ethanol exposed pups as assessed by tests on body righting, acoustic startle response, air righting, rearing and ultrasonic vocalization. In the open-field test the normally occurring behavioural difference between the sexes was not found in the prenatally ethanol exposed pups. Both sexes of the ethanol exposed pups behaved like the female controls suggesting deficient masculinization of the ethanol exposed male pups during foetal age. Biochemical analysis of the brains showed a decreased synthesis of serotonin and dopamine.
Collagen VI is a large, disulfide-bonded protein complex which is widely distributed in connective tissue. The constituent polypeptide chains (Mr = 110,000-140,000) consist of collagenous and noncollagenous segments, are degraded to chains of about half the size when collagen VI is solubilized by pepsin, and assemble to a unique pattern of oligomers. As revealed by electron microscopy, the triple-stranded protomer consists of a triple helix 105 nm in length flanked on each side by globular domains of similar size (diameter about 7 nm). Protomers are assembled to dimers by an antiparallel staggered alignment of triple-helical segments. This leads to inner regions, 75 nm in length, of two slightly supercoiled triple helices flanked by globular domains. At both sides 30-nm-long outer triple-helical segments emerge that are terminated by globules. Tetramers are formed from laterally aligned dimers that cross with their outer triple-helical segments in a scissors-like fashion. The same structures, except with much smaller globular domains, are found in pepsin-treated collagen VI. Disulfide-linked collagen VI produced by cultured fibroblasts has a size similar to that of genuine collagen VI found in tissue extracts. Larger forms of collagen VI are assembled from tetramers by end-to-end aggregation which because of an overlap of the outer segments brings all globular domains close together. This arrangement predicts microfibrillar structures in tissues with a periodicity of 100-110 nm and a diameter of 5-10 nm. Structures consistent with this proposal were indeed found by immunoelectron microscopy of placenta and aorta using the ferritin technique. Large, lateral aggregates of collagen VI microfibrils may in addition exist in cell cultures and tissues ("zebra collagen," "Luse bodies") and are presumably maintained by contacts between globular domains.
A procedure was developed for purifying the globular domain NC1 of basement membrane collagen from collagenase digests of a variety of tissues. The globule (Mr = 170,000) is a hexameric structure originating from two collagen IV molecules that are cross-linked at their COOH-terminal ends. Dissociation into subunits derived from alpha 1(IV) and alpha 2(IV) chains occurs at a pH below 4 and after denaturation (8 M urea). The subunits obtained include monomers (Mr = 28,000) and two different dimers (Da,Db) which are connected by disulfide bonds (Db) and/or nonreducible bonds (Da). Almost perfect reconstitution to hexamers is obtained in neutral buffer with mixtures of the subunits or purified dimers but not with purified monomers. Stabilization by dimer formation and other physical data suggest conformationally distinct segments within the subunits, which is also supported by a repeating subdomain structure deduced from cDNA sequences. Monocline crystals of NC1 give a sufficiently detailed X-ray diffraction pattern that should permit elucidation of the three-dimensional structure of the hexamer. Antibodies raised against the globular domain react with all subunits and mainly recognize epitopes stabilized by internal disulfide bridges and/or the hexameric assembly. Immunoprecipitation tests with these antibodies demonstrated a slightly larger subunit size of NC1 in PYS-2 cell culture and the rapid release of precursor-specific segments prior to secretion from the cells. Autoantibodies against mouse tumor NC1 were produced in mice and were detected both in the blood and as tissue-bound forms (kidney, lung). The autoantibody response is accompanied by certain pathological alterations mimicking Goodpasture's syndrome. The possible relationship between the two diseases is substantiated by reaction of Goodpasture antisera with the globular domain obtained from various tissue sources.