Imaging of the lumbar spine in spondylolysis and spondylolisthesis.
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Humans↗
Biomedical subjects
C George
Publications and source records attributed to C George.
Structure of an ether dimer of deoxydihydroqinghaosu, a potential metabolite of the antimalarial arteether.
C30H49O7, Mr = 518.69, triclinic, P1, a = 9.013 (2), b = 10.520 (2), c = 15.187 (3) A, alpha = 93.3 (2), beta = 93.73 (1), gamma = 95.88 (2) degrees, V = 1426.2 (5) A3, Z = 2, Dx = 1.21 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.65 mm-1, F(000) = 564, T = 295 K, final R = 0.043, wR = 0.042 for 3842 observed reflections. The dimer is formed such that the deoxyarteether moieties are cis to one another. Attempts to determine the absolute configuration of the molecule were inconclusive so the conformation corresponding to that found for qinghaosu was used for the refinement. Both halves of the dimer have the same chirality with five of the seven asymmetric carbons having an S conformation and two (C5 and C6) having an R conformation.
Antimalarials↗
Focal spinal muscular atrophy in two German shepherd pups.
Focal spinal muscular atrophy evolved rapidly in two German Shepherd pups 2 weeks after birth. By 1 month, the male and female littermates had developed a valgus deformity of the right forelimb, a flexed carpus, and arm and forearm muscle weakness and atrophy. In the male, less severe left forelimb weakness and wasting also occurred, and bilateral forelimb denervation potentials were recorded. Postmortem study of the male revealed asymmetric loss and degeneration of motoneurons in the cervical spinal cord intumescence. Degenerating neurons appeared vacuolated or chromatolytic. Chromatolysis was often peripheral and resulted from dispersion and loss of the free and attached ribosomes which normally from Nissl bodies. Although this focal neuronopathy was unlike motoneuron diseases described previously in animals, it resembled the asymmetric and unilateral, benign spinal muscular atrophies found in humans.
Animals↗
Fracture-associated osteogenic sarcoma and a mandibular osteoma in two goats.
An osteogenic sarcoma in association with a previously repaired fracture site and an osteoma were recorded in two aged Toggenburg and Toggenburg-cross goats. In one animal, five years after the surgical repair of a comminuted mid-shaft humeral fracture with an intramedullary pin, a sarcoma with osteoid production developed at the fracture site. A review of records revealed the previous occurrence of a mandibular osteoma inducing both subluxation of the temporal mandibular joint and contralateral mandibular deviation in a second animal. Such lesions are rarely documented in goats.
Animals↗
An aortic body carcinoma with multifocal thoracic metastases in a cat.
A necropsy performed on an aged cat with respiratory signs revealed a large white firm mass cranioventrally to the heart, and multiple similar masses scattered throughout the lungs, diaphragm, pericardial sac and intercostal muscles. The histological examination of the primary site and the metastases are consistent with a well-differentiated aortic body carcinoma.
Animals↗
Probes for narcotic receptor mediated phenomena. 15. (3S,4S)-(+)-trans-3-methylfentanyl isothiocyanate, a potent site-directed acylating agent for the delta opioid receptors in vitro.
Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfentanyl isothiocyanates [(3S,4S)-(+)-trans- and (3R,4R)-(-)-trans-4]. A single-crystal X-ray analysis of the 2,4,6-trinitrobenzenesulfonic acid salt of (+)-trans-3-methyl-N-phenyl-4-piperidinamine [(+)-trans-8] revealed it (and, therefore, 4) to have the trans configuration and the absolute configuration of (+)-trans-8 to be 3S,4S. The (+)-trans enantiomer of 4 was shown to be highly potent and about 10-fold more selective as an acylating agent than (-)-trans-4 for the higher affinity [3H]DADL (delta) binding site in rat brain membranes. In that assay, (+)-trans-4 and (+)-cis-4 were essentially equipotent as affinity ligands, and the levo enantiomers were considerably less potent. (+)-trans-4 was, thus, a potent, subtype-selective acylating agent for the delta opioid receptor in vitro. With membranes from NG108-15 neuroblastoma x glioma hybrid cells, containing only delta receptors, (+)-cis-4 was found to be a little more potent than (+)-trans-4. Similarly, (+)-cis-4 is the most effective inhibitor of adenylate cyclase in these membranes, (+)-trans-4 has weak activity, and the levo enantiomers are inactive. Only (+)-cis-4 was found to have antinociceptive activity in vivo.
Acylation↗
Alterations in the stereochemistry of the kappa-selective opioid agonist U50,488 result in high-affinity sigma ligands.
The synthesis and in vitro sigma receptor activity of the two diastereomers of U50,488 [(+/-)-2], namely, (1R,2S)-(+)- cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacet ami de [(+)-1] and (1S,2R)-(-)-cis-3,4-dichloro- N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide [(-)-1], are described. (+)-1 and (-)-1 were synthesized from (+/-)-trans-N-methyl-2-aminocyclohexanol [(+/-)-3]. Pyridinium chlorochromate (PCC) oxidation of the N-t-Boc-protected derivative of (+/-)-3 afforded (+/-)-2-[N- [(tert-butyloxy)carbonyl]-N-methylamino]cyclohexanone [(+/-)-5]. The sequence of enamine formation with pyrrolidine, catalytic reduction, N-deprotection, and optical resolution afforded (1R,2S)-(-)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(-)-10] and (1S,2R)-(+)-cis-2-pyrrolidinyl-N-methylcyclohexylamine [(+)-10]. The optical purity (greater than 99.5%) of (-)-10 and (+)-10 was determined by HPLC analysis of the diastereomeric ureas formed by reaction with optically pure (R)-alpha-methylbenzyl isocyanate. The absolute configuration of (-)-10 and (+)-10 was determined by single-crystal X-ray diffractometry of the bis-(R)-mandelate salt. Condensation of optically pure (-)-10 and (+)-10 with 3,4-dichlorophenylacetic acid furnished (+)-1 and (-)-1, respectively. Compounds (+)-1, (-)-1, (-)-2, and (+)-2 were compared for their binding affinities at kappa opioid, sigma, D2-dopamine, and phencyclidine (PCP) receptors in competitive binding assays using [3H]bremazocine ([3H]BREM) or [3H]U69,593, [3H]-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [[3H]-(+)-3-PPP], or [3H]-1,3-di(o-tolyl)guanidine ([3H]DTG), [3H]-(-)-sulpiride [[3H]-(-)SULP], and [3H]-1- [1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP), respectively. In the systems examined, (-)-2 exhibited the highest affinity for kappa receptors, with a Ki of 44 +/- 8 nM. However, (-)-2 also showed moderate affinity for sigma receptors, with a Ki of 594 +/- 3 nM [[3H]-(+)-3-PPP]. The (1R,2R)-(+)-enantiomer, (+)-2, had low affinity for both kappa and sigma receptors, exhibiting Ki values of 1298 +/- 49 nM at kappa ([3H]BREM) and 1270 +/- 168 nM at sigma [[3H]-(+)-3-PPP]. In contrast, the chiral cis compounds (+)-1 and (-)-1 showed high affinity for sigma receptors and negligible affinity for kappa opioid receptors in the [3H]BREM assay. Compound (-)-1 exhibited a Ki of 81 +/- 13 nM at sigma receptors [[3H]-(+)-3-PPP] and 250 +/- 8 nM ([3H]DTG).(ABSTRACT TRUNCATED AT 400 WORDS)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Comparative longitudinal study of 2 methods of scheduling maintenance visits: 4-year data.
116 subjects were recruited from a population of patients previously treated for adult periodontitis and maintained in periodontal health by means of periodic prophylaxes every 3-6 months. The subjects were divided into a control (C) and a test (T) group. A total of 33 patients in the T group and 47 in the C group completed the 4-year study. The C subjects were examined every 6 months and given a prophylaxis every 3 months. The patients in the T group were examined at similar intervals, but prophylaxes were administered according to the individualized scheme of Listgarten and Shiffter, on the basis of a differential microscopic count of subgingival bacterial morphotypes. Recurrent periodontitis was defined as an increase in probing depth of 3 mm or more from baseline measurements. Teeth so affected were sampled microbiologically when the diagnosis of recurrent disease was made and "exited" from the study for treatment. A control microbial sample was taken at the same time from a previously-defined pooled sample of non-affected surfaces with comparatively high, but stable probing depths. During a 4-year period, more than half of the subjects developed at least one recurrence of disease, and one-third of the subjects had 2 or more recurrences of periodontitis. Disease recurred on approximal surfaces 81% and on orovestibular surfaces 19% of the time. There were no significant differences in the rate of disease recurrence between the C and the T group, even though recall intervals in the T group at the 4-year examination averaged 19.4 months and an average of 30.6 months had elapsed since the previous prophylaxis. Both groups exhibited similar plaque index and gingival index scores, similar probing depth and attachment level measurements, and similar proportions of different bacterial morphotypes during the 4-year study. However, differences were noted between examinations for both groups with respect to most of these criteria. This study provides 4-year longitudinal data on the clinical and certain microbiological characteristics of a population of adult patients previously treated for moderate to advanced periodontitis, and subsequently placed on periodontal maintenance. The results indicate that some of these patients may remain in good periodontal health despite the lack of regular tri-monthly recall visits, and that microscopic monitoring of the subgingival microbiota may be of value in identifying these individuals.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Inactivation of gamma-aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid.
(Z)-4-Amino-2-fluorobut-2-enoic acid (1) is shown to be a mechanism-based inactivator of pig brain gamma-aminobutyric acid aminotransferase. Approximately 750 inactivator molecules are consumed prior to complete enzyme inactivation. Concurrent with enzyme inactivation is the release of 708 +/- 79 fluoride ions; transamination occurs 737 +/- 15 times per inactivation event. Inactivation of [3H]pyridoxal 5'-phosphate ([3H]PLP) reconstituted GABA aminotransferase by 1 followed by denaturation releases [3H]PMP with no radioactivity remaining attached to the protein. A similar experiment carried out with 4-amino-5-fluoropent-2-enoic acid [Silverman, R. B., Invergo, B. J., & Mathew, J. (1986) J. Med. Chem. 29, 1840-1846] as the inactivator produces no [3H]PMP; rather, another radioactive species is released. These results support an inactivation mechanism for 1 that involves normal catalytic isomerization followed by active site nucleophilic attack on the activated Michael acceptor. A general hypothesis for predicting the inactivation mechanism (Michael addition vs enamine addition) of GABA aminotransferase inactivators is proposed.
4-Aminobutyrate Transaminase↗
Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid.
Evidence for an enamine mechanism of inactivation of pig brain gamma-aminobutyric acid (GABA) aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid is presented. apo-GABA aminotransferase reconstituted with [3H]pyridoxal 5'-phosphate is inactivated by (S,E)-4-amino-5-fluoropent-2-enoic acid and the pH is raised to 12. All of the radioactivity is released from the enzyme as an adduct of the cofactor; no [3H]pyridoxamine 5'-phosphate is generated.
4-Aminobutyrate Transaminase↗
A trial of mezlocillin versus cefuroxime with or without metronidazole for the prevention of wound sepsis after biliary and gastrointestinal surgery.
A randomized controlled trial was undertaken to compare the role of mezlocillin, as the sole prophylactic agent, with a combination of cefuroxime and metronidazole in patients undergoing biliary and gastrointestinal surgery. No difference in wound infection rates was seen in patients following appendicectomy, biliary or gastro-oesophageal surgery. A significantly higher wound infection rate was seen in patients undergoing colorectal surgery who received mezlocillin alone (30.2%) compared with those receiving cefuroxime and metronidazole (11.5%): this rate was similar to that of historical placebo controls in other units. The wound infections seen in patients receiving mezlocillin alone were polymicrobial involving organisms of faecal origin, including non-sporing anaerobes which were predominantly sensitive to mezlocillin. Infections due to Staphylococcus aureus, resistant to mezlocillin, were more frequent in patients receiving mezlocillin and usually secondary in nature. We conclude that mezlocillin may be an effective sole prophylactic agent in appendicectomy but not in colorectal surgery; the possible reasons for failure to adequately prevent infection, following colorectal surgery, are discussed.
Biliary Tract Diseases↗
Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.
Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,4S,6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidine site. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.
Animals↗
Synthesis, configuration, and evaluation of two conformationally restrained analogues of phencyclidine.
Brown oxidation of cis-bicyclo[3.1.0]hexan-3-ol afforded bicyclo[3.1.0]hexan-3-one in 98% yield. Treatment of this ketone with either phenyllithium or phenylamagnesium bromide in ether at room temperature followed by solvolysis of the resulting alcohol in a mixture of trifluoroacetic acid, sodium azide, and chloroform gave a mixture of cis- and trans-3-azido-3-phenylbicyclo[3.1.0]hexanes. LAH reduction of this crude mixture of azides afforded a 1:3.5 mixture of cis- and trans-3-phenyl-3-bicyclo[3.1.0]hexylamine, respectively, in 51% overall yield from the alcohol. Separation of the mixture of amines by column chromatography followed by cyclization of each by heating at 60 degrees C in DMF solution with 1 equiv of 1,5-dibromopentane furnished the two conformationally restrained analogues of phencyclidine (PCP), cis- and trans-3-phenyl-3-piperidinylbicyclo[3.1.0]hexane (1 and 2, respectively), in high yield. Configurations were assigned on the basis of an X-ray crystallographic analysis of the cis isomer (1). Bond lengths and angles are similar to those found in PCP and its derivatives. Binding to PCP receptors and sigma sites as well as behavioral effects of 1 and 2 in rats was determined relative to PCP. In displacement of specifically bound [3H]TCP (1-[1-(2-thienyl)cyclohexyl]piperidine) from PCP receptors, 1 and 2 were nearly equipotent and about one-seventh as potent as PCP. These compounds were about one-fifth as potent as PCP in displacing [3H]-(+)-SKF 10,047 from its binding site. Calculation of the ED50 values of 1 and 2 for stereotyped behavior and ataxia indicated that they were about equipotent, and 2-3-fold less active than PCP.
Animals↗
Comparative effects of bisoprolol and acebutolol in smokers with airway obstruction.
1. The effects of single oral doses of 10 mg bisoprolol and 400 mg acebutolol on respiratory function were studied in nine smokers with airway obstruction in a double-blind, placebo-controlled experiment. 2. The effects of the drugs were assessed by measuring specific airway conductance (sGaw) for 3 h after their administration and by studying their interaction with the bronchodilator response to inhaled salbutamol. 3. sGaw did not change for 3 h after bisoprolol or acebutolol administration. The bronchodilator response to inhaled salbutamol was not affected by bisoprolol but significantly reduced by acebutolol (P less than 0.05 vs placebo). 4. Under these conditions, bisoprolol behaves like a selective beta 1-adrenoceptor antagonist but acebutolol exhibits less beta 1-adrenoceptor selectivity.
Acebutolol↗
Synthesis and absolute configuration of optically pure enantiomers of a kappa-opioid receptor selective agonist.
The enantiomers of U50,488, ligands highly selective for kappa-opioid receptors, have been prepared by a refined procedure and their optical purity demonstrated. The absolute configuration of (+)-trans-2-pyrrolidinyl-N-methylcyclohexylamine, a chemically versatile intermediate for synthesis of analogs of kappa-opioid receptor ligands with defined chirality, has been determined to be 1S,2S by X-ray crystallographic analysis. This intermediate has been used to synthesize the optically pure U50,488 enantiomers with known absolute configuration.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Hypercapnia and sleep O2 desaturation in chronic obstructive pulmonary disease.
There is a wide clinical spectrum in chronic obstructive pulmonary disease (COPD). The extremes of this spectrum, the "pink puffer" (PP) and "blue bloater" (BB) stereotypes differ in their degree of sleep hypoxemia and pulmonary hypertension. Most patients cannot be characterized as either PP or BB. The data amassed in the recent nocturnal oxygen therapy trial provide an opportunity to see to what extent differences in sleep oxygenation and hemodynamics in a large hypoxemic COPD population are related to awake hypoxemia and hypercapnia. From a large hypoxemic COPD population sleep SaO2 was examined in those with (PaCO2 greater than 44 mm Hg) and without (PaCO2 less than or equal to 44 mm Hg) hypercapnia. Hypercapnic patients (mean PaCO2 49.8 mm Hg) had the same PaO2 and degree of airflow obstruction as normocapnic patients (PaCO2 37.4 mm Hg) but had far greater sleep hypoxemia (measured by mean sleep SaO2, low sleep SaO2, and awake-low sleep SaO2, p less than 0.05). In addition, arterial blood gases of the large sleep O2 desaturaters were compared with those of the small desaturaters; PaO2 was similar in both groups, whereas PaCO2 was different (p less than 0.01). Two common subsets of hypoxemic patients were also compared; one was hypercapnic and overweight, the other normocapnic and hyperinflated. We found that patients in the hypercapnic group had far worse sleep hypoxemia, although they had better lung function. We conclude that hypercapnia is a marker for sleep O2 desaturation in hypoxemic COPD.
Aged↗
Depth-focused radio frequency coils for MR imaging.
Surface coils improve signal-to-noise ratios by the simple expedient of reducing field of view. The uniformity of response of these coils is poor, since signal reception is weighted toward the surface of the object, which generally is of least interest. Furthermore, whole-section transmitter coils excite the subject uniformly, so that weak signals are detected from far regions. A dual-coil arrangement permits avoidance of these problems by combining the nonuniform excitation and reception characteristics of two surface coils.
Equipment Design↗
Long duration of response with vindesine-mitoxantrone-mitomycin (VMMc) combination chemotherapy in metastatic breast cancer: a pilot phase II study.
A total of 39 women with metastatic breast cancer entered a pilot phase II study of the vindesine-mitoxantrone-mitomycin (VMMc) combination chemotherapy. Most of them had received previous chemotherapy [including doxorubicin (27 patients)] for their primary or metastatic disease. The VMMc drugs were given at usual doses. Hematologic side effects were the most serious, leading mainly to leukopenia (five episodes of infection were successfully treated). A 33% partial response rate was obtained (95% confidence limits, 18%-48%), with a median duration (not yet reached) of greater than 510 days (range, 150-720) for the overall population. The median for pretreated patients was greater than 420 days (range, 150-720) which compares favorably with those previously reported in similar patients treated by mitomycin and vindesine or vinblastine.
Adult↗