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7786428
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Inflammatory pseudotumour of the central nervous system: clinicopathological study of one case and review of the literature.
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A 58-year-old male who had been diagnosed as having polymyositis was found to have a mass in the fourth ventricle. This mass showed features of an inflammatory pseudotumor. This lesion has been described in many parts of the body including the central nervous system. This case showed some features different from the previously reported cases in the central nervous system (i.e. presence of necrosis and association with polymyositis) which may throw some light on the pathogenesis of the condition. Inflammatory pseudotumour is most likely to be caused by an exaggerated immunological process and is sometimes associated with high levels of serum immunoglobulin.
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7786425
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Pituitary function after selective adenomectomy for Cushing's disease.
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This retrospective analysis was undertaken to determine whether selective adenomectomy for Cushing's disease can achieve acceptable cure rates while causing minimal pituitary dysfunction. Tumour size, histology and pituitary function were evaluated in 34 consecutive patients (26 F: 8 M, mean age 33.6 years) undergoing transphenoidal adenomectomy for Cushing's disease from 1975 to 1992. Follow-up averaged 5.8 years. Cure was defined as resolution of symptoms and signs and normalization of urinary cortisol excretion. Sixty-three per cent of patients achieved cure after selective adenomectomy, repeat adenomectomy cured an additional four patients. Twenty-eight per cent required bilateral adrenalectomy and/or pituitary irradiation. Postoperative pituitary function remained completely intact in 81%. Secondary hypogonadism occurred in 8%, hypothyroidism in 155 and permanent diabetes insipidus in 4%. There was recurrence in 26% after a mean of 4.6 years (range 1-7). It is concluded that selective adenomectomy can achieve acceptable cure rates with a low prevalence of postoperative hypopituitarism, although an increase of recurrence may be the result of conservative surgery.
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7786426
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The presence of progesterone receptors in arachnoid granulations and in the lining of arachnoid cysts: its relevance to expression of progesterone receptors in meningiomas.
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Progesterone receptors (PR) were identified with an enzyme immunoassay in cytosols from human arachnoid granulations and arachnoid cysts. Meningiomas presumably originate from subdural endothelium which is abundantly present in these structures. In the three cases studied, oestrogen receptors were absent. The presence of PR in subdural endothelium may provide further ground for the expression of PR in meningiomas.
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7786424
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Fatal postoperative 'pituitary apoplexy': its cause and management.
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Two cases of giant pituitary tumours are reported. The patients underwent transcranial operation, one by the pterional and one by the subfrontal route. Only partial resection of the tumour was possible in each instance for various reasons. Acute worsening of the clinical condition in the immediate postoperative phase led to reoperation in both patients. In one case the reoperation was carried out within 45 min of the closure of the wound and in the other after 12 h. Massive swelling of the tumour with evidence of haemorrhagic infarction was a surprise finding. After a turbulent postoperative phase, both patients died. We postulate that these patients developed pituitary apoplexy of the residual tumours.
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7786422
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Post-traumatic brain abscess: experience of 36 patients.
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Thirty-six patients with post-traumatic brain abscess were managed over 18 years. They constituted 9.3% of all brain abscesses encountered during the same period. The head injury was associated with an external compound fracture in 20, internal compounding in three and was closed in 13 patients. The mean interval between the time of injury to presentation with an abscess was 113 days. This did not differ significantly in patients with closed and compound head injury, and amongst patients who had wound sepsis and with clean wounds after the injury. The occurrence of focal neurological deficit was more frequent in patients with a closed injury (p < 0.05). Twenty patients underwent primary excision of the abscess with recurrence of the abscess in one patient. Of the 14 patients in whom the abscess was initially aspirated, eight patients required a subsequent excision. Excision was required in 18 patients (94.7%) with external compound injury, five (50%) of those with closed injury and in all patients with internally compound injuries. Two patients had 'coned' and died before they could be operated upon. The operative mortality in the absence of signs of herniation preoperatively was 12.5% in patient with compound injury and none among patients with closed head injury.
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7786421
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CT assessment of subarachnoid haemorrhage. A comparison between different CT methods of grading subarachnoid haemorrhage.
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A number of different CT classifications of subarachnoid haemorrhage (SAH) were applied to a consecutive series of 50 patients with aneurysmal SAH. The best correlation with delayed ischaemic deficits (DID) was obtained with a score formed by the sum of the individual cisternal grades except that of the cortical subarachnoid space. The findings emphasize the significance of the extent of the SAH, rather than the presence of a localized cisternal clot with regard to the development of DID.
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7786420
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Trigeminal neuralgia treated by microvascular decompression: a long-term follow-up study.
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Since 1976, 133 patients treated by posterior fossa microvascular decompression (MVD) for trigeminal neuralgia (TN) have been followed-up prospectively to determine the incidence of recurrent TN. The follow-up period was between 6 months and 15 years, with 60 patients having been follow-up for more than 5 years. Of these patients, 71% have remained pain-free, while 29% have suffered a major or minor recurrence. Of patients who developed recurrent TN, 90% did so within 2 years of operation. No patients who were pain-free up to 5 years after operation subsequently developed recurrent TN. Recurrent TN was more likely to occur when the operative findings did not show nerve root distortion or displacement, or when the age of onset was less than 35 years.
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7786418
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Cervical myelopathy caused by pseudogout.
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A case of pseudogout manifesting as a cervical myelopathy is presented. Surgery can offer the definitive treatment with removal of the compressing crystalline mass. This diagnosis should be considered in a progressive myelopathy in the elderly person shown to have extradural compression, even in the absence of other stigmata of gout.
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7786411
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Tau protein kinase I/GSK-3 beta/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brain.
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Previously, tau protein kinase I/glycogen synthase kinase-3 beta/kinase FA(TPKI/GSK-3 beta/FA) was identified as a brain microtubule-associated tau kinase possibly involved in the Alzheimer disease-like phosphorylation of tau. In this report, we find that the TPKI/GSK-3 beta/FA can be stimulated to phosphorylate brain tau up to 8.5 mol of phosphates per mol of protein by heparin, a polyanion compound. Tryptic digestion of 32P-labeled tau followed by high-performance liquid chromatography and high-voltage electrophoresis/thin-layer chromatography reveals 12 phosphopeptides. Phosphoamino acid analysis together with sequential manual Edman degradation and peptide sequence analysis further reveals that TPKI/GSK-3 beta/FA after heparin potentiation phosphorylates tau on sites of Ser199, Thr231, Ser235, Ser262, Ser396, and Ser400, which are potential sites abnormally phosphorylated in Alzheimer tau and potent sites responsible for reducing microtubule binding possibly involved in neuronal degeneration. The results provide initial evidence that TPKI/GSK-3 beta/FA after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau and neuronal degeneration in Alzheimer disease brains.
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7786415
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[Attitudes of Bolivian pharmacy distributors in a case of diarrhea].
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In order to learn the recommendations given for a case of diarrhea by persons who sell medications at pharmacies, interviewers visited pharmacies in three Bolivian cities and said they had a child suffering from diarrhea. Less than 2% of the vendors recommended using oral rehydration salts, increasing fluid intake, or consulting a doctor. Most of them recommended antibiotics, antidiarrheals, or both. Oral rehydration salts were not available in nearly two-thirds of the establishments visited, and those that had the salts rarely offered them. This study revealed the lack of integration of these professionals into the Health Secretariat's training program, and as a result activities were initiated to solve this problem.
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7786413
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Stable oncogenic transformation induced by microcell-mediated gene transfer.
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Oncogenes have been identified using DNA-mediated transfection, but the size of the transferable and unrearranged DNA, gene rearrangement and amplification which occur during the transfection process limit the use of the techniques. We have evaluated microcell-mediated gene transfer techniques for the transfer and analysis of dominant oncogenes. MNNG-HOS, a transformed human cell line which contained the met oncogene mapping to human chromosome 7 was infected with retroviruses carrying drug resistance markers and used to optimize microcell preparation and transfer. Stable and drug-resistant hybrids containing single human chromosomes as well as the foci of the transformed cells containing the activated met oncogene and intact human chromosomes were obtained. Hybridization analysis with probes (i.e. col1A2, pJ3.11) mapping up to 1 Mb away from met shows that the cells from the individual foci contain different amounts of apparently unrearranged human DNA associated with the oncogene, and the microcell-generated transformants retain more distal markers than those observed in either DNA- or chromosome-mediated transfers. In conjunction with other techniques, microcell fusion should be useful for gene mapping as well as the study of gene function and expression in cell transformation and malignancy.
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7786412
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PDI-, PPI- and chaperone-catalyzed refolding of recombinant human IL-2 and GM-CSF.
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The studies on PDI-, PPI- and chaperone-catalyzed refolding of recombinant human IL-2 and GM-CSF show that PDI can prevent the mismatch of disulfide bonds and formation of aggregates by interchains linkage; furthermore, PDI can correct the mismatching of disulfide bonds in IL-2 isomers. PPI can increase the rate of folding reaction while chaperone can prevent the aggregation during the folding process. In addition, there is a synergistic effect between them.
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7786410
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Chemical modification of tryptophan residues in alpha-neurotoxins from Ophiophagus hannah (king cobra) venom.
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Two alpha-neurotoxins, Oh-4 and Oh-7, from the king cobra (Ophiophagus hannah) venom were subjected to Trp modification with 2-nitrophenylsulfenyl chloride (NPS-Cl). One major NPS derivative was isolated from the modified mixtures of Oh-4 and two from Oh-7 by HPLC. Amino acid analysis and sequence determination revealed that Trp-27 in Oh-4, and Trp-30 and Trp-26 and 30 in the two Oh-7 derivatives, were modified, respectively. Sulfenylation of Trp-27 in Oh-4 caused about 70% drop in lethal toxicity and nicotinic acetylcholine receptor-binding activity. Modification of Trp-30 in Oh-7 resulted in the decrease of lethal toxicity by 36% and binding activity by 61%. The activities were further lost when the conserved Trp-26 in Oh-7 was modified. Sulfenylation of the Trp residues did not significantly affect the secondary structure of the toxins as revealed by the CD spectra. These results indicate that the Trp residues in these two long alpha-neurotoxins may be involved in the receptor binding.
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7786409
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Symmetric interspecies hybrids of mouse and human hemoglobin: molecular basis of their abnormal oxygen affinity.
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Interspecies hybrids of HbA and Hb from mouse C57BL/10 [alpha 2M beta 2H and alpha 2H beta 2M (H = human, M = mouse)], representing 19 and 27 sequence differences per alpha beta dimers (as compared with human alpha beta dimer) have been generated in vitro. The efficiency of the assembly of the interspecies hybrids by the alloplex intermediate pathway is about twofold higher than the low-pH-mediated subunit approach. The interspecies hybrids exhibit a cooperative O2 binding. The intrinsic O2 affinity of mouse Hb is slightly lower than HbA, while the 2,3-diphosphoglycerate (DPG) effect is comparable. Interestingly, the interspecies hybrid alpha 2M beta 2H has high O2 affinity (compared to either human or mouse Hb), while the interspecies hybrid alpha 2H beta 2M exhibits a very low O2 affinity. These results suggest that the mouse beta chain generates a tetramer with very low oxygen affinity. However, the complementarity of the mouse alpha and beta chains generates a set of unique interactions that compensate for the low-oxygen-affinity propensity of the mouse beta chain. DPG binds the tetramer in the central cavity formed by the two beta subunits, hence the DPG effects on the interspecies hybrids should be as in the parent molecule. However, the results of the present study demonstrate that the DPG binding pocket is influenced by the nature of the alpha chain present in the tetramer. The mouse alpha chain reduces considerably the DPG right shift of the O2 affinity of the human beta-chain containing hybrid.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786407
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Complete amino acid sequence of Proteus mirabilis PR catalase. Occurrence of a methionine sulfone in the close proximity of the active site.
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The catalase of Proteus mirabilis PR, a peroxide-resistant (PR) mutant of Proteus mirabilis, binds strongly NADPH, which is a unique property among known bacterial catalases. The enzyme subunit consists of 484 amino acid residues for a mass of 55,647 daltons. The complete amino acid sequence was resolved through the combination of protein sequencing, mass spectrometry, and nucleotide sequencing of a PCR fragment. The sequence obtained was compared with that of other known catalases. Amino acids of the active site are all conserved as well as essential residues involved in NADPH binding. Among the amino acids interacting with the heme, a methionine sulfone was found at position 53, in place of a valine in most other catalases. The origin of oxidation of this methionine is unknown, but the presence of this modification could change iron accessibility by large substrates or inhibitors. This posttranslational modification was also demonstrated in the wild-type P. mirabilis catalase.
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7786408
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Expression and purification of recombinant cynomolgus monkey cholesteryl ester transfer protein from Chinese hamster ovary cells.
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Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from high- and low-density lipoproteins to triglyceride-rich lipoproteins, and reciprocally mediates triglyceride transfer. The gene for cynomolgus monkey CETP was expressed in serum-free CHO culture with 2 micrograms/ml insulin as its only exogenous protein supplement. Cell growth was facilitated by immobilizing the CHO cells in alginate beads. Recombinant CETP (rCETP) was purified 176-fold with a three-step protocol resulting in a 60% final yield as measured by a fluorescent CETP activity assay. Typically, 3.4 mg of rCETP was purified from 1700 ml of media by affinity-gel chromatography involving Reactive Red 120 (RR120) followed by concanavalin A Sepharose 4B and rechromatography on RR120. SDS-PAGE shows a single broad band of M(r) ranging from 68,000 to 74,000 which immunoreacts in Western blot analysis. Amino acid analysis and protein sequencing of the purified protein agree with the theoretical amino acid composition and sequence of cynomolgus CETP.
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7786406
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Purification and characterization of a 60-kDa protein from oat, formerly known as a TCP1-related chaperone.
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Recently, Mummert et al. [Nature 363, 644-648 (1993)] isolated a proposed TCP1-related chaperone. Here we report several findings concerning the protein which they sequenced. Two similar N-terminal sequences were obtained from this abundant 60-kDa protein. Internal sequences were also acquired by protease digestion. Initially it was believed the protein was able to completely inhibit citrate synthase aggregation, but later purifications demonstrated that the 60-kDa polypeptide lacked both chaperone activity and the previously reported kinase activity [Grimm et al., Planta 178, 199-206 (1989)]. It is now our belief that this protein is neither a chaperone nor a kinase.
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7786405
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The molecular basis for N-glycosylation in the 11S globulin (legumin) of lupin seed.
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Ion exchange-HPLC under denaturing conditions was used to purify to homogeneity the major M(r) 44,000 alpha subunit of lupin seed (Lupinus albus, L.) 11S storage globulin (legumin). The carboxymethylated subunit was digested with trypsin and the peptide fragments separated by reverse phase HPLC. Only one glycosylated peptide reacting with concanavalin A was identified by dot-blotting. Its amino acid sequence allowed the location of this peptide within a highly conserved region in proximity to the N-terminus of the alpha subunits of the 11S globulins from other seeds. The unique presence of a serine residue in a sequence N-X-S of lupin 11S globulin, compared with all other 11S proteins, allows it to be the only protein of this class to bear covalently linked carbohydrate.
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7786402
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Preliminary characterization of epithelial root sheath cells in vitro.
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Murine root sheath cells from CD-1 mice were isolated and propagated in culture in both monolayer and tridimensional system using basement membrane components as substrata. Cells were grown for a period of seven days. The epithelial cells cultured in monolayer exhibited the typical cobblestone-like feature and also were cytokeratin positive when they were immunostained with the specific antibody. The histological analysis of the cells cultured in basement membrane components revealed differentiated behavior of the cells, and they organized in a round structure with a center of material probably representing keratin. Also the cells differentiated and organized into a squamous stratified epithelia, with a basal, intermedium and superficial layers. The preliminary data obtained with this model could be useful as a new approach to study root formation in the murine periodontum.
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7786404
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New electrophysiological approaches to the suprachiasmatic circadian pacemaker.
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Suprachiasmatic nucleus contains the main circadian pacemaker for mammals rhythmical behavior and physiology. In this paper we revise recent experimental advances on electrophysiological studies to suprachiasmatic circadian pacemaker in rodents. Our growing understanding of the electrophysiology of this nucleus will help to elucidate the clock organization and its input and output mechanisms.
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7786401
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Increased oxygen radical and high-dietary-carbohydrate pancreatic damage.
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These data suggest that an improved understanding of the relationship between high dietary carbohydrate and the rate of lipid peroxidation may give some insight into possible treatment modalities for pancreatic damages and may shed light on molecular mechanisms underlying certain pathological processes. High dietary carbohydrate lesions are age related and induced alterations on ceruloplasmin, phospholipids, total proteins, copper and zinc serum levels. Significantly increased serum and pancreatic amylase, and lipoperoxide determinations were observed in 20 month old rats. Cu-Zn superoxide dismutase was decreased in these animals. Daily injection of Cu-Zn superoxide dismutase conjugated with polyethylene glycol (SOD-PEG) prevented the serum and pancreatic changes, indicating that superoxide radical is an important intermediate to high dietary carbohydrate lesion.
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7786403
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Distribution of mast cells in the tracheal tissue components of the guinea pig and its bearing on the Schultz-Dale reaction.
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The distribution of mast cells in the tracheal tissue components and its bearing on anaphylaxis was studied in the guinea pig. According to a statistical analysis (Nested ANOVA) the density found in the tissue elements showed the following gradation (mean +/- SE): muscle (299.7 +/- 61.6 cells/mm3) < serosa (802.7 +/- 131.2 cells/mm3) < submucosa (24283.5 +/- 2549.2) < mucosa (48066.4 cells/mm3 +/- 7837.4). Regardless of their location in tissue elements, the cell density in a zone far from the muscle was larger than in a zone close to the muscle. Considering the histamine release capability of mast cells, the density found either in muscle or in its surroundings does not account for the mediation theory unless some postulates ad hoc are introduced. A direct biophysical mechanism is possibly involved. Another alternative is a reflex to histamine, since there is preponderant location of mast cells in mucosa and submucosa.
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7786400
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Protein malnutrition on suprachiasmatic nucleus cells in rats of three ages.
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The effects of prenatal and postnatal protein malnutrition on the major and minor somatic axes of the suprachiasmatic nucleus (SCN) cells of the rat were investigated. Female rats were fed either 6%, 8% or 25% casein diet 5 weeks before mating, during gestation and lactation. After weaning the pups were maintained on the same diet until sacrifice at 30, 90 or 220 days of age. The major and minor axes in fusiform, multipolar and ovoid cells were measured in Nissl-stained SCN slices. Although the 8% diet group displayed significant reductions in fusiform and ovoid cells, the 6% diet group showed the most intense reductions in cell size of the three cell types. In the 6% diet group, cell size was significantly lower at 30 days but the difference with the other nutritional groups ameliorated at 90 days and almost reached control values at 220 days. These data suggest that malnutrition maintained during gestation and postnatal life reduces the somatic size of SCN cells. This alteration may be a morphological substrate underlying sleep and behavioral circadian alterations observed in malnourished rats.
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7786398
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Binding to DNA and cytotoxic evaluation of ascididemin, the major alkaloid from the Mediterranean ascidian Cystodytes dellechiajei.
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The isolation of ascididemin from the Mediterranean ascidian Cystodytes dellechiajei is described. This alkaloid consists of a planar pentacyclic chromophore which was investigated for its DNA-binding and cytotoxic properties. Spectroscopic measurements provided evidence that the drug intercalates into DNA. DNase I footprinting assays indicated that the binding of ascididemin to GC-rich sequences is favoured over binding to AT-rich and mixed sequences. Chemical probes were used to detect ligand-induced structural changes in DNA. The alkaloid induces a hyper-reactivity of the DNA towards potassium permanganate, but not towards diethylpyrocarbonate, just as is the case with ethidium bromide; it has little effect on the catalytic activities of topoisomerases I and II. Ascididemin exhibits marked cytotoxicity towards human leukaemic cells in vitro and appears to be practically equally toxic for drug-sensitive and multidrug-resistant cell lines. The results suggest that DNA, but not topoisomerases, may represent the critical cellular target at which this marine alkaloid exhibits its potent cytotoxic properties in vitro.
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7786399
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Novel quinone antiproliferative inhibitors of phosphatidylinositol-3-kinase.
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The inhibition of phosphatidylinositol-3-kinase (PtdIns-3-kinase), protein kinase C and c-Src protein tyrosine kinase by a series of halogenated naphthoquinones and quinoline quinones related to the plant-derived naphthoquinones juglone and methyljuglone, which inhibit protein kinase C, has been investigated. Some of the compounds inhibited PtdIns-3-kinase at micromolar concentrations and below. PtdIns-3-kinase inhibition was time dependent and could be prevented by endogenous thiol. The compounds were only weak inhibitors of PtdIns-4-kinase. Some of the compounds inhibited protein kinase C, but c-Src protein tyrosine kinase was only weakly inhibited. In intact cells, PtdIns-3-kinase was only partly inhibited by concentrations of the halogenated quinones that inhibited cell growth. Some halogenated quinones showed in vivo antitumor activity without accompanying toxicity, while methyljuglone was without in vivo antitumor activity. Halogenated quinones may have multiple biochemical effects in the cell that could contribute to their cytotoxic and antitumor effects. Inhibition of PtdIns-3-kinase by the halogenated quinones may provide a lead for the development of more potent and specific inhibitors.
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7786397
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Synthesis and biological evaluation of basic side chain derivatives of Analog II as pure antiestrogens and antitumor agents.
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In an effort to prepare effective non-steroidal antiestrogens without intrinsic estrogenicity and with greater antagonism than those of the triarylethylenes (tamoxifen; TAM) four N-substituted (Z)-1,1-dichloro-2-[4-(2-aminoethoxy)phenyl]-3-phenylcyclopropa ne derivatives of the antiestrogen, Analog II, in which the basic side chains contain cyclic (piperidino and piperazino) and non-cyclic (dimethyl amino and diethyl amino) moieties, were synthesized. These compounds were prepared from an intermediate methanesulfonyloxyethoxy side chain ester of 1,1-dichloro-2,3-cis-diphenylcyclopropane using their respective side chain bases in triethylamine and acetonitrile. The gem-dichloro-cis-diarylcyclopropane derivatives were tested for their ability to inhibit the growth-stimulating effect of estradiol on immature mouse uteri and the growth of estrogen receptor (ER)-positive MCF-7E3, ER-negative MDA-MB-231 and the ER-positive MCF-7LY2 antiestrogen-resistant breast cancer cells in culture. The introduction of the various aminoethoxy side chains into Analog II did not improve its ER-binding affinity. Like Analog II, the derivatives did not exhibit any intrinsic estrogenicity, and compounds 9 and 10 antagonized estradiol action more completely than the parent compound. None of the compounds potentiated the uterine weight gain from the stimulating dose of estradiol (0.03 micrograms). Derivatives 9 (150 micrograms), 10 (150 micrograms) and 11 (150 micrograms) had uterine mean weights significantly below the estradiol-treated group, and were better antagonists than Analog II and MER25 at the same concentrations. All compounds exhibited a statistically significant (P < 0.01) reduction in control growth (antitumor activity) from 0.01 to 10 nM concentration in the MCF-7E3 cells. At 10 nM concentration, 8 (66%) and 9 (64%) had the greater antitumor activity over 10 (58%) and 11 (58%). No activity in this cell line was observed for Analog II, TAM and ICI 182,780. Antitumor action was also demonstrated in the MDA-MB-231 cells for all derivatives at 1.0 microM dose, with 9 having the greatest (27%) inhibition of control growth, followed by 8 (20%), 10 (18%) and 11 (12%). Analog II and ICI 182,780 had no antitumor activity in this cell line, while TAM exhibited only 8% inhibition. In the MCF-7E3 cell line at 1.0 microM, 9 exhibited 86% inhibition of the estradiol-stimulated growth (antiestrogenic activity), followed by 8 (64%), 10 (52%) and 11 (21%).(ABSTRACT TRUNCATED AT 400 WORDS)
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7786396
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Antineoplastic agents 322. synthesis of combretastatin A-4 prodrugs.
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Combretastatin A-4 (1a), the principal cancer cell growth-inhibitory constituent of the Zulu medicinal plant Combretum caffrum, has been undergoing preclinical development. However, the very limited water solubility of this phenol has complicated drug formation. Hence, derivatives of the combretastatin A-4 (1a) 3'-phenol group were prepared for evaluation as possible water-soluble prodrugs. As observed for combretastatin A-4, the sodium salt (1b), potassium salt (1c) and hemisuccinic acid ester (1e) derivatives of phenol 1a were essentially insoluble in water. Indeed, these substances regenerated combretastatin A-4 upon reaction with water. A series of other simple derivatives (1d, 1f-j) proved unsatisfactory in terms of water solubility or stability, or both. The most soluble derivatives evaluated included the ammonium (1l), potassium (1m) and sodium (1n) phosphate salts, where the latter two proved most stable and suitable. Both the potassium (1m) and sodium (1n) phosphate derivatives of combretastatin A-4 were also found to exhibit the requisite biological properties necessary for a useful prodrug. Sodium salt 1n was selected for drug formulation and further pre-clinical development.
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7786395
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Synthesis and biological evaluation of amino-substituted benzo[f]pyrido[4,3-b] and pyrido[3,4-b]quinoxalines: a new class of antineoplastic agents.
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In order to study the structure-activity relationships in the series of new intercalating polycyclic agents, 1-amino-substituted pyrido[3,4-b]quinoxalines, benzo[f]pyrido[4,3-b]quinoxaline derivatives bearing a dibasic side chain and their benzo[f]pyrido[3,4-b] isomers have been synthesized. Biological evaluation was carried out for topoisomerase I and II inhibition, and for in vitro and in vivo antitumor properties in several models. Results demonstrate that appropriately substituted benzo[f]pyrido[4,3-b]quinoxaline derivatives are inhibitors of topoisomerase I and II, and have significant antitumor properties in various experimental models. In addition, the most active compounds appear to be minimally recognized by tumor cells expressing the multidrug resistance phenotype.
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7786394
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The identification of mistakes in road accident records: Part 2, Casualty variables.
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It has been acknowledged that there are many mistakes in recording the casualty variables on the police accident report forms. This study shows how a computer-based linkage of police and hospital records can be used routinely to identify the mistakes for the variables of casualty age, gender, and severity. The level of omissions and misidentifications were 0.4% for gender, 12.2% for severity, and 15.7% for age. The number of records that had age omitted or coded incorrectly was not significantly greater for seriously injured casualties than for those who were slightly injured. This system could be effectively used to code casualty severity using medical information instead of police judgement.
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7786393
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The identification of mistakes in road accident records: Part 1, Locational variables.
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The current method of checking police-reported road accident data involves a rigorous process of manual and computer validation, with the objective of removing all the errors that exist on the accident report forms. This paper shows how a geographic information system (GIS) can be used to identify mistakes that exist in several locational variables once this process has been undertaken. It compares items contained on the accident report form with accurate highway feature information obtained from other sources. There were less than 10% of mistakes for the variables of district, speed limit, road class, and road number; less than 20% for junction control, junction detail, and pedestrian crossing facilities; and over 20% for carriageway type. If highway data were routinely entered onto a GIS by all British highway authorities, the above variables might not need to be entered by the police on their accident report forms.
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7786392
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The relationship of the retail availability of alcohol and alcohol sales to alcohol-related traffic crashes.
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The research literature on the relationship of alcohol consumption to motor vehicle crash risk clearly implicates the importance of minimizing the use of alcohol in conjunction with the operation of motor vehicles. However, there has been relatively little documentation of the direct impact of changes in beverage-specific alcohol sales on the most common surrogate for alcohol-involved traffic crashes, single-vehicle nighttime fatalities. Similarly, there have been few studies of the relationship between the physical availability of alcohol and fatal crash rates which have concurrently controlled for differences in alcohol sales. Indeed, the possibility that reduced availability might lead to increases rather than decreases in fatal crashes (due to increased driving after drinking) has not been adequately tested. This paper presents a series of analyses of time-series cross-sectional data from 38 states over 12 years to evaluate the impact of changes in alcohol sales and the physical availability of alcohol upon single-vehicle nighttime fatal crashes. The results of the study showed, first, that independent of a number of economic and demographic covariates, rates of single-vehicle nighttime fatal crashes were most strongly related to sales of beer and less so to sales of spirits and wine. Second, net of beverage-specific alcohol sales, the physical availability of alcohol was not related to measurable changes in fatal crash rates. Thus, reductions in availability intended to reduce alcohol sales and problems would not appear to increase traffic-related crashes through increased driving exposure.
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7786391
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Analysis of official economic valuations of traffic accident fatalities in 20 motorized countries.
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Official economic valuations (costs) of a traffic accident fatality in 20 motorized countries are described. The economic valuation per fatality varies from 0.87 million Norwegian kroner to 17.80 million kroner. The mean value is 5.69 million kroner. An attempt is made to explain the differences in official cost estimates. The valuation method used in estimating the costs has major importance for the level of costs. Recently, a number of motorized countries have accepted the willingness-to-pay approach as the basis for the economic valuation of traffic accident fatalities. In these countries, this has led to major upward revisions of previous cost estimates.
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7786390
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Safety implications of extending some Canadian Motor Vehicle Safety Standards to light trucks and vans.
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The primary objective of this research was to evaluate the implications of extending specific Canadian Motor Vehicle Safety Standards (CMVSS) to light trucks and vans (LTVs). This was accomplished through the examination of the potential safety-related benefits of these standards comparing the injury frequencies and severities of the light trucks and vans and the passenger cars (PCs). The standards considered, which currently apply to passenger cars but not to LTVs, are the head restraint (CMVSS 202), side door strength (CMVSS 214), and roof crush strength (CMVSS 216) standards. The comparison was effected by means of logit models developed from multidimensional tables with injury frequency and severity as dependent variables. There are indications that installing head restraints in light trucks and vans could reduce or prevent minor neck injuries and that modest benefits could be achieved by extending the roof crush standard to the LTVs. It was also determined that the side door strength standard may not necessarily be as beneficial to LTVs in conditions in which the vehicle is struck on the side by another LTV. It is suggested that the general public be made aware of the differences in safety standards between LTVs and PCs.
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7786389
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Bicyclist deaths and fatality risk patterns.
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While there are almost 1,000 bicyclist deaths in the United States every year, there has been little formal analysis of the fatal risk patterns of bicyclists. In large part, this is because there has been little information available on riding exposure. The purpose of this article is to determine and quantify the relative risks of death for bicyclists according to age, gender, and daylight conditions. Relative risks are estimated by comparing data on the characteristics of fatally injured bicyclists with estimates of riding exposure from a recent national survey of bicyclists in the United States. The results suggest substantially higher fatality risks for males, for bicyclists over the age of 44, and for bicyclists who ride after dark. Discussion of the results includes implications regarding differences in the fatal and nonfatal injury risks associated with bicycle use.
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7786387
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Preventable death classification: interrater reliability and comparison with ISS-based survival probability estimates.
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The purpose of the study was to compare the injury-related threat to survival estimated by the Injury Severity Score (ISS) and a committee of experts. The charts of 116 (73 fatalities and 43 survivors) patients with severe injuries were reviewed. A committee of nine clinicians classified each case as survivable, potentially survivable, and nonsurvivable based on anatomical descriptors, mechanism of injury, and patient's age. Majority was used to determine the final committee classification. Based on the ISS values, cases were classified as survivable (9-24), potentially survivable (25-49), and nonsurvivable (> 49). The results showed poor interrater reliability among the nine clinicians with an overall intraclass correlation coefficient of 0.43. The ISS-based classification had high agreement with the final committee classification (overall weighted kappa = 0.71). Lower agreement was observed for falls and with increasing number of injuries. This study has demonstrated no additional benefit for using a committee to classify injury severity on the basis of anatomical damage over applying ISS-based survival probabilities. The continued use of the ISS is supported.
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7786388
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Impact of the 65 mph speed limit on accidents, deaths, and injuries in Illinois.
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At the end of April 1987, Illinois raised the speed limit from 55 to 65 mph on rural interstates and limited-access highways. This paper examines the effects of this change. It applies ARIMA techniques to a monthly time series of accidents, injuries, and fatalities dating from five years before the limit increase to four years after. Two types of rural highways are examined: those where the speed limit was raised and those where it remained at 55 mph. The impact of higher limits on mean speeds, speed variance, traffic diversion, traffic generation, speed spillover, and issues of benefits and costs are considered. The findings suggest the higher limit led to 300 additional accidents per month in rural Illinois, with associated increases in deaths and injuries. This impact was apparent on both 65 and 55 mph roads. There is some evidence of traffic diversion from 55 to 65 mph highways plus traffic generation and speed spillover.
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7786385
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A study of injury-producing crashes on median divided highways in southwestern Ontario.
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The University of Western Ontario Accident Research Team investigates every fatal crash, and approximately one out of every 50 personal-injury crash, within a defined geographic area of three counties. Over a seven-year period, the team investigated 107 collisions (62 fatal and 45 personal injury) that occurred on median-divided highways. These crashes were representative of over 2,300 collisions on the highways involving 81 fatalities and injury to over 3,200 vehicle occupants. Vehicle loss of directional control prior to any impact occurred in 55 of the 62 fatal cases and in 36 of the 45 personal-injury cases. In 36 fatal cases and 17 personal-injury cases loss of control was initiated after a vehicle travelled from the roadway onto the gravel shoulder. Rollover collisions were the most frequent collision type investigated and comprised 25 fatal and 25 personal-injury cases. Unrestrained occupants made up 24 of the 29 rollover fatalities with 96% of these unrestrained occupants being ejected from the vehicle. Collision with an oncoming vehicle after median-crossover occurred in 26 fatal cases. These crashes were usually frontal or side impacts characterized by extensive vehicle damage and massive intrusion into the occupant compartment. Severe head injury (AIS 5 or greater) predominated as the cause of death in all collision types.
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7786386
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Field observation of advance warning/advisory signage for passive railway crossings with restricted lateral sightline visibility: an experimental investigation.
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This study evaluated a newly proposed series of signs intended for passive crossings with restrictions to lateral sightline visibility. These signs provide advance warning of a crossing and the restriction to lateral visibility. In addition, the signs advise motorists to come to a complete stop before crossing. Motorist behaviour was examined before and after installation of these signs at a rural passive crossing. A second site was observed in parallel to control partially for any confounding effects. Results indicated that motorists reduced speed and searched approach quadrants longer at points in the approachway after installation of the signs. However, there was no reliable increase in the number of motorists coming to complete stop, engaging in search behaviours, or classified as safe. The results are discussed in terms of reasons for the lack of compliance with the sign advisory.
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7786384
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A five-year experience with severe injuries in elderly patients.
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Recent reports of injury in elderly patients document that aggressive care is justified. Our experience indicates that geriatric injury differs from that of other trauma patients. All patients entered into a large urban trauma center registry over a five-year period were analyzed. Variables reviewed included demographics, trauma indices, mechanism of injury, mean number of hospital days, and morbidity and mortality for patients under 60 years old and for geriatric patients defined as those aged 60 and above. There were 3,064 patients in the reviewed group, of whom 243 qualified for geriatric analysis. Blunt injuries in males were the most typical scenario. Failure to use safety belts and alcohol intoxication persist into the geriatric age group (83% and 13%, respectively). Trauma indices including Injury Severity Score (ISS) were slightly greater in the geriatric group (27 versus 23) as compared to younger patients; plus geriatric patients tolerated head injury less well (GCS in those who died 6.7 versus 4.6, respectively; p < 0.001). Mortality in the geriatric group was 31% while being 17.1% in the younger group (p < 0.005). Days in the hospital were 20 for the geriatric compared to 13 for the younger group (p < 0.025). Infections and chest complications were twice as common in the elderly and dysrhythmias were five times more frequent. Elderly patients constitute 8% of the trauma population and suffer a magnitude of injury at least comparable to the general population. Their mortality is approximately 50% above the population as a whole and morbidity twice as common, accounting for the prolonged hospital stay.
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7786383
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Who's in the car? Passengers as potential interveners in alcohol-involved fatal crashes.
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This article assesses the promise of motor vehicle passengers as interveners to prevent drinking and driving. It describes data from the U.S. Fatal Accident Reporting System (FARS), which indicate that most alcohol-involved fatally injured drivers (70% of males, 66% of females) were not accompanied by "adult" passengers (16 or older), and alcohol involvement among those passengers present appears to be high (80%). Nonetheless, in approximately 5% to 10% of cases it appears that sober or relatively "unimpaired" passengers could have served as interveners in alcohol-involved driving incidents. Passenger interveners may hold the most promise among teenagers, where passengers in general and unimpaired passengers in particular appear to be most prevalent.
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7786382
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Abandonment of mandatory jail for impaired drivers in Norway and Sweden.
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In 1988 and 1990, respectively, Norway and Sweden adopted legal reforms including abandonment of mandatory jail sentences for persons driving with BACs above specific limits. Interrupted time-series analysis finds that in both countries traffic deaths diminished simultaneously with the reforms, consistent with the understanding that Scandinavian success in reducing impaired driving does not depend upon mandatory jail.
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7786380
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Gender-associated differences in matriculating and graduating medical students.
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Data from the 1993 Matriculating Student Questionnaire (MSQ) and the 1994 Medical School Graduation Questionnaire (GQ) of the Association of American Medical Colleges were investigated for differences in responses between men and women. Notable differences were discovered, particularly with regard to career plans and experiences during medical school. Findings from the GQ include that a higher proportion of women rated curricular coverage of numerous subjects inadequate and that women students more frequently reported mistreatment during medical school. Women were also more likely than men to work in clinics serving the indigent and to complete a primary care clerkship. Over 30% of the 1994 women seniors, compared with 18% of the men, planned to pursue generalist careers. The authors discuss the gender-associated differences, with reference to previous studies, and conclude that medical educators should ensure that women have access to the same skill-development opportunities that men do and to a humane learning environment. Moreover, educators should examine what adaptations can encourage students of both genders to develop an ethic of "social responsibility."
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7786381
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Influencing factors on the injury severity of restrained front seat occupants in car-to-car head-on collisions.
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The results of 319 cases of belt-restrained front seat car occupants (234 drivers and 85 passengers) from 241 vehicles in car-to-car head-on collisions were examined. Ninety-five occupants were uninjured, 195 sustained a total injury severity of Maximum Abbreviated Injury Score (MAIS) 1-3 and 29, MAIS 4-6. There were 27 fatalities, and the main causes of death were polytrauma and hemorrhage. The main factors influencing occupant injury severity were: the energy equivalent speed (EES); the change of velocity (delta upsilon); the maximum deformation depth; and the collision angle. With an EES > 50 km/h fatal injuries can be expected, and above 60 km/h no occupant remained uninjured. The results of a multivariate analysis were: EES influenced the injury severity at all body locations except the spinal cord; occupant position effected only head injury severity, with drivers being more severely injured; occupant age influenced the injury severity at the thorax, abdomen, and extremities and MAIS as well. Age was a further factor influencing injury severity, e.g. with an EES of 50 km/h the probability of being fatally injured was 30%-45% higher for occupants over 59 years than those under 20.
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7786374
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Influence of medical school applicants' demographic and cognitive characteristics on interviewers' ratings of noncognitive traits.
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Interviews are commonly used to measure noncognitive traits of medical school applicants. The present study investigated the influence of knowledge of applicants' cognitive abilities on interviewers' ratings of noncognitive traits. Academic and demographic predictors of interview ratings of applicants' noncognitive traits were examined at the Medical University of South Carolina College of Medicine during two years: 1992, when applicants' Medical College Admission Test (MCAT) total scores and undergraduate grade-point averages (GPAs) were available to interviewers; and 1993, when MCAT and GPA data were not available. In 1992, 226 applicants met study criteria (i.e., they received ratings from three interviewers in addition to having MCAT and GPA data on file); in 1993, 245 applicants met the criteria. Step-wise regression analyses were conducted to measure the influences of seven independent variables on applicants' interview ratings. Two-way analyses of variances and t-tests were used to determine the effects of gender of applicants and interviewers. Cronbach's alpha coefficients were used as measures of interviewers' reliability. GPA was the best predictor for both years but accounted for double the amount of variance in interview ratings in 1992 (15.7%) compared with 1993 (7.4%). The reliability coefficients for the interviewers were .496 for 1992 and .473 for 1993. If the goal of the medical school admission interview is to assess noncognitive traits independently from academic skills, the authors recommend that MCAT and GPA data not be available to interviewers during interviews. The authors also found that gender and race influenced interview ratings in accordance with affirmative-action goals. Finally, the authors found that interview scores were only moderately reliable across different interviewers. They discuss ways to increase their reliability.
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7786375
|
A prospective, randomized trial of a six-week ambulatory medicine rotation.
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Medical schools are placing increased emphasis on training students in the ambulatory setting, but few studies show the benefit or academic risk of such innovation. The authors studied the effect of such a new rotation with a rigorous study design. From a group of 166 third-year students at the Uniformed Services University of the Health Sciences F. Edward Hébert School of Medicine assigned in 1990-91 to do six weeks of their third-year medicine clerkship at Walter Reed Army Medical Center, 106 volunteers were randomized to six weeks either on the usual rotation on the general medicine wards (69 students) or to a new ambulatory rotation (37 students). Multiple pre- and postclerkship parameters were used to evaluate clerkship skills and knowledge; eventual internship choice was determined. The randomization was successful. Postclerkship performances were the same in (1) the medicine subject examination of the National Board of Medical Examiners, (2) a multiple-choice test in interpreting laboratory results, (3) blinded rating by an expert panel of the quality of final written histories and physical exams, (4) blinded rating by an expert panel of the students' written case analyses of their own patients, and (5) a written multiple-step examination of problem-solving ability. Any differences between groups favored the ambulatory group. An increase in choice of primary care internships among students randomized to the ambulatory rotation was not significant. It is possible to study innovative rotations using a prospective, randomized design. Substituting a six-week block ambulatory experience for a ward rotation did not decrease students' abilities to write up or analyze complex cases.
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7786373
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Analysis of the cost of training residents in a community health center.
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Currently one federal program funds community health centers (CHCs) to provide services in underserved communities, and a second supports development of primary care teaching programs. Teaching CHCs respond to both program's goals, but their development is hindered by restrictive regulations of the two programs and lack of information regarding cost. Spreadsheet software was used to develop a model that allocates cost components of a CHC-based residency. Productivity and staffing data from a teaching CHC program were used to estimate the cost of training and its sensitivity to selected variables. Data from 1992 through 1994 were collected from the family practice residency sponsored by the Brown University School of Medicine, the Memorial Hospital of Rhode Island, and the Blackstone Valley Community Health Center. An educational supplement of $13.21 per visit would be required for the program to be cost-neutral relative to staff. The cost of outpatient training for a resident averaged $13,935 per year. Residents would "break even" if they saw patients at 19% above the average rate recommended by the residency review committee. If staff physicians instead of residents had provided the patient care, the CHC would have saved $6,171 per resident. Additional savings from improved physician recruiting and decreased turnover would increase the value of the program to the CHC. Cost was most sensitive to resident productivity, precepting arrangements, nursing staff support, and staff turnover. Developing graduate medical education programs in CHCs can be a cost-effective way of increasing the pool of appropriately trained primary care physicians and increasing health care access for underserved populations. If teaching CHCs are to expand, provisions will need to be made for adequate reimbursement of their costs.
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7786371
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Indicators of the educational effectiveness of subspecialty training programs in internal medicine.
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To identify markers within the subspecialty educational process in internal medicine that are associated with greater improvements in knowledge and skill. Candidates for the 1991 cardiovascular disease examination of the American Board of Internal Medicine (ABIM) were matched to the fellowship programs they attended, and their performances on the internal medicine examination of the ABIM, demographic data, and performances on the cardiovascular disease examination were averaged within each program. Information on the programs themselves was also available. The variables were divided according to whether they controlled for input to the training programs, were indicators of educational process, or served as the outcome measure. Analyses were restricted to the 140 programs for which complete information was available and that had four or more candidates who took the cardiovascular examination (97 programs were excluded). The multiple correlation between all measures and scores on the cardiovascular disease examination was .80. Forty-five percent of the explained variance is attributable to previous performance on the internal medicine examination alone. The remaining 55% is shared by the educational indicators and the input measure or explained by the indicators alone. Among the indicators, location of medical school, length of fellowship training, ratings of overall clinical competence, fellow-to-faculty ratio, and number of subspecialties in the same institution made small contributions on their own. Program size, university affiliation, and period of approval by the residency review committee contributed little. The data are clear that indicators of educational process such as fellow-to-faculty ratio, longer periods of training, and performance during fellowship can generate greater gains in knowledge and judgment than would be expected if fellows merely built on their abilities at the time of entry to training. Such indicators may be useful if changes in health care delivery require reducing the numbers of specialty and subspecialty training positions.
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7786372
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Validity of three clinical performance assessments of internal medicine clerks.
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To analyze the construct validity of three methods to assess the clinical performances of internal medicine clerks. A multitrait-multimethod (MTMM) study was conducted at the Case Western Reserve University School of Medicine to determine the convergent and divergent validity of a clinical evaluation form (CEF) completed by faculty and residents, an objective structured clinical examination (OSCE), and the medicine subject test of the National Board of Medical Examiners. Three traits were involved in the analysis: clinical skills, knowledge, and personal characteristics. A correlation matrix was computed for 410 third-year students who completed the clerkship between August 1988 and July 1991. There was a significant (p < .01) convergence of the four correlations that assessed the same traits by using different methods. However, the four convergent correlations were of moderate magnitude (ranging from .29 to .47). Divergent validity was assessed by comparing the magnitudes of the convergence correlations with the magnitudes of correlations among unrelated assessments (i.e., different traits by different methods). Seven of nine possible coefficients were smaller than the convergent coefficients, suggesting evidence of divergent validity. A significant CEF method effect was identified. There was convergent validity and some evidence of divergent validity with a significant method effect. The findings were similar for correlations corrected for attenuation. Four conclusions were reached: (1) the reliability of the OSCE must be improved, (2) the CEF ratings must be redesigned to further discriminate among the specific traits assessed, (3) additional methods to assess personal characteristics must be instituted, and (4) several assessment methods should be used to evaluate individual student performances.
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7786369
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The potential of computerized representations of anatomy in the training of health care providers.
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The purpose of anatomy education is to develop the skills for anatomical reasoning, which is a requirement for performing a number of clinical tasks. Anatomical reasoning integrates an understanding of the three-dimensional (3-D) geometry of the body and its parts (the spatial domain of anatomical information) with an understanding of functional, developmental, pathological, and other relationships among anatomic entities (the symbolic domain of anatomical information). Traditional methods in anatomy have substantial shortcomings for representing and integrating these two information domains. Computer-based methods of knowledge representation have a great potential for overcoming the shortcomings and for promoting anatomical reasoning. To realize this potential, there is a need for (1) establishing 3-D electronic atlases of the human body; (2) generating models of symbolic anatomical information, and (3) developing computer programs (user interfaces) that integrate these knowledge sources and serve the needs of trainees and practitioners in different fields of the health sciences. The Digital Anatomist Program at the University of Washington has begun to build such a client-server framework for anatomical information, and its application for biomedical education is being evaluated.
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7786368
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A model alcohol and other drug use curriculum for pediatric residents.
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While alcohol and other drug (AOD) use is a major health risk for adolescents in the United States, there is a paucity of AOD training for pediatric residents. In 1991-92, the University of Wisconsin Medical School developed an experiential, community-based AOD curriculum for pediatrics residents. The curriculum included resident participation in a community-based AOD adolescent assessment and intervention program, interactive didactic sessions, role-playing practice, and interviewing skills sessions. The residents who participated in the curriculum (n = 25) were compared with a control group (n = 19). Evaluation included pre- and post-curriculum written tests, objective structured clinical examinations, and residents' ratings of the curriculum components. The residents who participated showed significant gains in AOD knowledge, utilization of screening techniques, and clinical management skills as compared with the controls. The residents gave positive ratings to all curriculum components. This well-received curriculum can serve as a national model both for AOD education in pediatrics and for curriculum development in other areas of adolescent health-risk-taking.
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7786367
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The NRMP matching algorithm revisited: theory versus practice. National Resident Matching Program.
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The authors examine the algorithm used by the National Resident Matching Program (NRMP) in its centralized matching of applicants to U.S. residency programs ("the Match"). Their goal is to evaluate the current NRMP matching algorithm to determine whether it still fulfills its intended purpose adequately and whether changes could be made that would improve the Match. They describe the basic NRMP algorithm and many of the variations of the matching process ("match variations") incorporated over the last 20 years to meet participants' requirements. An overview of the current state of the theory of preference matching is presented, including descriptions of the characteristics of stable matches in general, program-optimal and applicant-optimal matchings, and strategies for formulating preference lists. The characteristics of the current NRMP algorithm are then compared with the theoretical findings. Research conducted long after the original NRMP algorithm was devised has shown that an algorithm that produces stable matches is the best approach for matching applicants to positions. In the absence of requirements to satisfy match variations, the NRMP's deferred-acceptance algorithm produces a program-optimal stable match. When match variations, such as those handled by the NRMP, must be introduced, it is possible that no stable matching exists, and the resulting matching produced by the NRMP algorithm may not be program-optimal. The question of program-optimal versus applicant-optimal matchings is discussed. Theoretical and empirical evidence currently available suggest that differences between these two kinds of matchings are likely to be small. However, further tests and research are needed to assess the real differences in the results produced by different stable matching algorithms that produce program-optimal or applicant-optimal stable matches.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786366
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A reexamination of the NRMP matching algorithm. National Resident Matching Program.
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Most graduating medical students in the United States find their first professional appointments through the National Resident Matching Program (NRMP). This service receives rank-order lists of preferences from students and from hospitals, and then generates final assignments of students to hospitals through the use of a specific computerized matching algorithm. The author uses recent findings from the mathematics and economics literatures to demonstrate three difficulties with the NRMP's matching algorithm and the official descriptions thereof. First, the algorithm favors hospitals over students, a feature known to the NRMP since at least 1976, but, in the author's opinion, not made clear in NRMP literature for students. Second, the author argues that the NRMP's justification that its algorithm mimics orderly, noncentralized admission processes is not correct. Institutions operating under non-centralized procedures must typically make more initial offers than there are positions, in the realization that some fraction of their offers will be declined. This arrangement enlarges the choices available to many applicants, and thereby benefits them, whereas the NRMP's algorithm unrealistically assumes that no institution would ever send out any extra offers. Third, the NRMP's algorithm contains incentives for students to misrepresent their true preferences when constructing their rank-order lists. This feature is a substantial disadvantage of the current algorithm and is incorrectly described in literature distributed to students and in published articles from the NRMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786359
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The pediatric inguinal hernia: is contralateral exploration justified?
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To determine if contralateral inguinal hernia exploration is justified we decided to study our experience with 161 consecutive cases who underwent bilateral repair during a 30 months period. 61% of the population were infants younger than two years of age, and 19% premature babies. 69 pts presented with an RIH, 47 with an LIH and 45 pts with BIH. 16% suffered an episode of preoperative incarceration which were all reduced satisfactorily and operated promptly. A positive contralateral finding (either a hernial sac or a patent processus vaginalis) was identified in 74% RIH and 72% LIH patients upon exploration. No incidence of testicular edema/atrophy, vas deferens injury, or recurrence was reported in the six-year follow-up of the study. Statistical analysis of the contralateral findings during surgery with sex, gestational age and age at operation showed that females and infants younger than two months of age had a higher probability of having positive findings. We could not show that prematurity or left-sided hernias were associated with a higher positive contralateral rate. The major benefit of contralateral exploration is based on the fact that it allows discovery and elimination of a patent processus vaginalis so a hernia cannot develop subsequently. We conclude by establishing certain criteria that justifies the routine contralateral exploration of the pediatric hernia: the surgeon should be experienced in child care, associated conditions should not increase the surgical risks significantly, time-consuming dissections of the cord structures should be discouraged, and the operating time should be kept to a minimum.
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7786357
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[Risk management in the hospital industry].
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The author provides an introduction to the risk management process in the hospital industry as well as explains some of the basic elements in a risk management program in such industry. The author also explains the factors to be evaluated in a risk management program.
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7786356
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Group B streptococcal disease in pregnancy.
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Group B Streptococcal (GBS) infection in the pregnant female represents a challenging and often complex scenario which may cause deleterious effects in the neonate. In this paper we present three case reports of GBS infection in neonates with different outcome. A comprehensive review of the history, microbiology, clinical presentation and therapy guidelines is presented. Early diagnosis and institution of therapy are the most important factors which may have an impact on maternal and neonatal outcome.
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7786355
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Dengue fever with thrombocytopenia: studies towards defining vulnerability of bleeding.
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To define the period of greater vulnerability of bleeding in patients with Dengue fever in reference to the onset of their constitutional symptoms and the laboratory abnormalities. In a retrospective study we reviewed the records of all patients admitted to San Pablo Medical Center in 1991 with a diagnosis of Dengue Fever or Hemorrhagic Dengue. All patients with a platelet count of less than 125,000 were included for analysis. The exclusion criteria included the presence of systemic disorders which may influence the platelet count, and patients without documentation regarding the presence of constitutional symptoms suggestive of viral illness. A total of 101 patients were analyzed of which only 74 were included in the study. All patients had fever and chills; skin rash, asthenia and general malaise was seen in over 50% of patients. Over 70% of patients had recovery of their platelet count, and most had their maximal thrombocytopenia within the 5th day and 8th day from the onset of constitutional symptoms. Leukopenia was seen in over 70% of patients with its lowest level within the 5th and 8th day from the onset of the constitutional symptoms. Significantly prolonged partial thromboplastin time was seen in 11% of the patients. Proteinuria was seen in 22% of the patients, 38% of which had it within the first 4 days of the onset of constitutional symptoms and also noted on the 5th and 6th day. Alteration in liver enzymes were noted in 47% of patients, with a maximal severity distributed in all time frames. Hypoalbuminemia was present in 28% of the patients, of these 67% presented within the first 4 days from the onset of constitutional symptoms. The pulse rate was usually normal in spite of the patient's dehydration and fever. We identified three phases that define the sequence of events seen in the majority of patients with Dengue Fever and Thrombocytopenia. These are: 1. proteinuria and hypoalbuminemia; 2. maximal cytopenia; 3. bradycardia and liver enzyme elevation. We believe this information is useful in the management of patients with Dengue Fever and thrombocytopenia.
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7786354
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Changing trends in adenotonsillectomy at San Pablo Hospital 1983 vs. 1993.
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The purpose of this paper is to review the changing trends in Adenotonsillectomies performed in San Pablo Medical Center during the last ten years. We have reviewed using a 25 variable questionnaire all patients undergoing this surgical procedure during the first six months in 1983 and compared the information with the patients having this procedure during the first six months of 1993. We conclude that the number of interventions, the indications, prior medical history and cost effects have changed substantially. Our data supports the accuracy of some of the trends being reported in the literature regarding this surgical intervention.
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7786353
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Laser assisted surgery: the San Pablo experience.
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Two thousand plus (2,000+) assisted laser surgical procedures were performed between July 1986 and November 1993. Multiwavelength specialties: Argon, CO2 and NdYAG usage include: general surgery, thoracic surgery, neurosurgery, ophthalmology, and gynecology. 65% of the patients were female whose ages range from 6 to 105 years. Endoscopic vs. handheld procedures ratios 1:1. In 95% of the cases attended, the procedures were performed for benign conditions. The office hospital usage distribution was 60-40%. The office morbidity was 0.8% (16 out of 2,000 cases) and a mortality of 0.15% (3 out of 2,000 cases). A reported 100% safety compliance was seen. Laser assisted surgery is a safe, effective and reliable option available to the surgeon's armamentarium. It appears that in some procedures it will allow shorter hospital stays and an earlier return of the patient to his/her normal routine.
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7786350
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Anti-tuberculous therapy and acute liver failure.
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The incidence of tuberculosis has been increasing since 1987, exposing a greater number of patients to the risks of three potentially hepatotoxic drugs, isoniazid, rifampicin, and pyrazinamide. Awareness of potentially severe drug hepatotoxic reactions is vital because fulminant hepatic failure is a devastating and often fatal condition without liver transplantation. We report four cases of fulminant hepatic failure caused by rifampicin, isoniazid, or both. These cases highlight the need for stricter adherence to and review of current guidelines on liver function tests after starting anti-tuberculous therapies.
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7786349
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Carbohydrate, fat, and protein condition similar flavor preferences in rats using an oral-delay procedure.
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Flavor preferences conditioned by carbohydrate (Polycose), protein (casein hydrolysate), and fat (corn oil) were compared using an oral-delay training method. In Experiment 1 separate groups of food deprived rats were trained to associate a CS+ flavor (e.g., grape-saccharin) with the delayed (10 min) presentation of isocaloric carbohydrate, protein, or fat sources. A CS- flavor (e.g., cherry-saccharin) was paired with the delayed presentation of an unflavored saccharin solution. In subsequent two-bottle tests the carbohydrate, protein, and fat trained groups displayed significant preferences for the CS+ over the CS-. In Experiment 2 each rat was trained to associate two new flavors with two of the three nutrients (e.g., orange with carbohydrate, and strawberry with protein). In subsequent two-bottle tests the rats equally preferred the two nutrient-paired flavors. Experiment 3 compared the preferences for the new CS+ flavors vs. the original CS-flavor. The rats displayed similar preferences for carbohydrate-, protein- and fat-paired CS+ over the CS-. The similar preferences obtained with the three different nutrients support the view that preference conditioning is mediated by the nutrients' caloric value. Other studies suggest, however, that nutrient-specific signals are also involved in the conditioning process.
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7786348
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Treadmill exercise training and estradiol differentially modulate hypothalamic-pituitary-adrenal cortical responses to acute running and immobilization.
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It is generally believed that physical fitness promotes health by attenuating responsiveness to other stressors. The experimental evidence for this belief is limited and does not extend to interactions between the hypothalamic-pituitary-adrenal cortical (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. We tested the hypothesis that treadmill exercise training would lead to an estrogen-dependent hyporesponsiveness of the HPA axis that would generalize to immobilization stress. Ovariectomized female Sprague-Dawley rats (N = 74) that had been treadmill trained (TT) or sedentary for 6 weeks received intramuscular injections of estradiol benzoate (Eb) or sesame oil on each of 3 days prior to 15 min of acute treadmill running or immobilization. Plasma (adrenocorticotrophin) (ACTH), (corticosterone) (B) and (prolactin) (PRL) were determined from trunk blood by radioimmunoassay and compared in a 2 group (TT vs. sedentary)-by-2 treatment (Eb vs. oil)-by-2 acute stressor (running vs. immobilization) design. Home-cage (HC) animals (N = 24) provided baseline hormone levels. ACTH and B levels were elevated after stressors in animals treated with either Eb or oil compared to HC, but increases in PRL after stressors were dependent on Eb. Treadmill exercise training led to an attenuation of ACTH and prolactin to running, but the attenuation did not generalize to immobilization. In contrast, treadmill exercise training led to a hyperresponsiveness of ACTH. Treadmill training did not modulate prolactin responses to immobilization. The modulating effects of the estradiol treatment are consistent with an interaction of the HPA and HPG axes in response to stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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7786345
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[Anti-inflammatory effects of cromones in asthma].
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The cromone family comprises sodium cromoglycate and the more recently developed nedocromil sodium. Nedocromil sodium prevents the bronchial obstruction induced by a variety of stimuli, including antigen. When given before antigen inhalation, nedocromil sodium prevents the early and late reaction and the increase in bronchial hyperresponsiveness. It is still effective in preventing the late phase when given after antigen exposure. These effects may result from the action of nedocromil sodium on inflammatory cells observed in vitro, particularly mast cells and eosinophils. When inhaled regularly, nedocromil sodium improves symptoms, especially in moderate asthma, decreases bronchial obstruction and reduces bronchial hyperreactivity. Bronchial biopsy studies have shown a decrease in activated eosinophils during prolonged nedocromil sodium treatment, suggesting that the clinical benefit results from an antiinflammatory effect of the drug. More recently, it has been suggested that nedocromil sodium may act on membrane chloride channel involved in activation of many cell types. In vitro data have shown a decrease in IgE production by isolated mononuclear cells, suggesting new therapeutic potential to be studied clinically.
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7786341
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Tetanus and botulinum neurotoxins are zinc proteases specific for components of the neuroexocytosis apparatus.
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Tetanus and botulinum neurotoxins bind to nerve cells, penetrate the cytosol, and block neurotransmitter release. Comparison of their amino-acid sequences shows the presence of the highly conserved His-Glu-x-x-His zinc-binding motif of zinc-endopeptidases (HExxH). Atomic absorption measurements of clostridial neurotoxins show the presence of one atom of zinc/toxin molecule bound to the light chain. The toxin-bound zinc ion is essential for the neurotoxins inhibition of neurotransmitter release in Aplysia neurons injected with the toxins. Phosphoramidon, a very specific inhibitor of zinc-endopeptidases, blocks the intracellular activity of the clostridial neurotoxins. Highly purified preparations of the light chain of tetanus and botulinum B and F neurotoxins cleaved specifically VAMP/synaptobrevin, an integral membrane protein of small synaptic vesicles, both in vivo and in vitro. From these studies, it can be concluded that the clostridial neurotoxins responsible for tetanus and botulism block neuroexocytosis via the proteolytic cleavage of specific components of the neuroexocytotic machinery.
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7786332
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Folate status, women's health, pregnancy outcome, and cancer.
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Key observations by Dr. Lucy Wills 65 years ago have led to the identification of folate as a nutrient essential for the prevention of megaloblastic anemia of pregnancy. The more recently discovered relationships of folate status to cervical dysplasia, neural tube defects, and atherosclerosis are reviewed here.
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7786333
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[Abuse potential during use and withdrawal psychosis after treatment with the hypnotic zolpidem (Stilnoct)].
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Three cases are presented. Withdrawal symptoms and ultimately psychosis developed in two cases following cessation of the hypno-sedative zolpidem. Two cases involve dependence upon and abuse of the drug; in one, a well-known alcoholic, it was abused in combination with alcohol, the other had prior well-known dependence on sedative hypnotics. One patient had chronic dysphoria and one encephalopatia toxica. Adverse effects such as withdrawal symptoms, dependence and abuse have not previously been reported in relation to zolpidem. Chemically unrelated to benzodiazepines, zolpidem is thought to have fewer adverse effects, but shares a pharmacokinetic profile with the benzodiazepine triazolam. It is advised that normal criteria for the prescription of benzodiazepines also be used when prescribing non-benzodiazepine sedatives and hypnotics, as they act upon the same receptor, namely the benzodiazepine-GABA-chloride complex.
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7786324
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Chromosome mapping and organization of the human beta-galactoside alpha 2,6-sialyltransferase gene. Differential and cell-type specific usage of upstream exon sequences in B-lymphoblastoid cells.
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The human beta-galactoside alpha 2,6-sialyltransferase (EC 2.4.99.1) (SiaT-1) gene is localized to human chromosome 3 (q21-q28) by Southern analysis of somatic cell hybrids and by in situ hybridization of metaphase chromosomes. Comparative analysis between the human and the previously reported rat SiaT-1 genomic sequences demonstrates precise conservation of the intron/exon boundaries throughout the coding domains. Furthermore, there is extensive inter-species sequence similarity in some of the exons that contain information only for the 5'-leader regions. Human genomic sequences were also analyzed to reconcile reported differences in the 5'-untranslated region in SiaT-1 mRNAs. In cultured cell lines of the B-lineage, Reh, Nalm-6, Jok-1, Ball-1, Daudi, and Louckes, the study demonstrates that three upstream exons, Exons(Y+Z) and Exon(X), are mutually exclusively utilized, resulting in at least two distinct populations of SiaT-1 mRNA being synthesized. None of these exons is present in the SiaT-1 mRNA isotype expressed in HepG2 human hepatoma cells. In all B-lymphoblastoid cell lines examined, the basal level SiaT-1 mRNA is maintained by the expression of an isotype containing the Exons(Y+Z) sequence. The slightly smaller SiaT-1 mRNA, which contains the Exon(X) sequence but not Exons(Y+Z) sequence, is synthesized at a high level and found only in Jok-1, Daudi, and Louckes, the cell lines with mature B-cell phenotype. The study also provides further evidence that induced SiaT-1 expression accompanies the appearance of CDw75, a putatively sialylated cell surface epitope and a marker of human mature B-lymphocytes. The SiaT-1 induction is the result of the appearance of a novel form of SiaT-1 mRNA isotype.
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7786322
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[Open access upper endoscopy. Can the practice be improved?].
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150 patients who were referred to the open access endoscopical unit in a county hospital for upper gastrointestinal examination were evaluated. The aim was to answer the following questions: How often is this upper GI-endoscopy of value for medical treatment of the patient, and is "open access endoscopy" a practical system? In order to obtain a more reliable diagnosis it is necessary to examine the patient without delay, and thereby avoid the masking effect of H-2 blockers and omeprazole. More attention to anamnestic risk factors would improve case selection. In many cases it is possible to rely on X-ray examination, and thus reduce the burden on the endoscopy unit and allow for instant endoscopy service.
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7786321
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[Nonchemical methods of modifying substrates for studying biopolymers with atomic force microscopy].
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Two simple procedures of DNA molecule fixation on mica for following imaging by the atomic force microscopy were developed. The distinctive features of the procedures are their simplicity, absence of chemical modification stages, and the possibility to obtain the images in air under relative high humidity. Comparison of the features of the images obtained indicated that the procedures developed were competitive with the procedures earlier suggested.
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7786320
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[Modification of pyrimidine nucleosides using nicotinic acid derivatives].
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Interaction of nicotinoyl chloride in situ with 2'-deoxyuridine, its 3'-O-acetyl-, or 5'-O-trityl derivatives led to 3'-O-nicotinoyl-, 5'-O-nicotinoyl-, 3',5'-di-O-nicotinoyl-, and N3,3'-di-O-nicotinoyl-2'-deoxyuridine. Similarly, 5'-O-nicotinoyl-6-azauridine resulted from the reaction of 2',3'-O-ethoxymethylidene-6-azauridine followed by the deprotection. Reaction of 5'-amino-5'-deoxy-2',3'-O-ethoxymethylidene-6-azauridine with nicotinic acid in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline followed by the cleavage of the 2',3'-O-protecting group gave 5'-deoxy-5'-nicotinamido-6-azauridine. The same compound was obtained from 5'-amino-5'-deoxy-6-azauridine and N-succinimidyl nicotinate. Structures of the compounds obtained were corroborated by 1H NMR spectra. It is shown that 3',5'-di-O-nicotinoyl-2'- deoxyuridine and 5'-deoxy-5'-O-nicotinamido-6-azauridine are cytotoxic toward CaOv cells in vitro (CE50 10(-5) M).
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7786319
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[Dependence of the level of gene expression in E. coli on the structure of the translation initiation segment (TIR)].
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The expression levels of genes that are transcribed to give mRNAs with identical leader sequences and even with identical extended coding regions may differ considerably. In order to determine the mechanism of this phenomenon, secondary structures of some mRNAs synthesized from a series of expression plasmids were studied. It was shown that the effect of the mRNA secondary structure in the translation initiation region on the initiation efficiency is due not only to the hairpin formation in this region but also to long-range interactions. When complementary structures tighter than those resulted from the interaction of regions SD, UB1, UB2, and DB with 16S rRNA are formed, the efficiency of the translation initiation and, consequently, the expression level decrease.
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7786318
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[Synthesis of a cyclic enkephalin analog with prolonged action].
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A cyclic analog of enkephalin, cyclo(Lys-Tyr-DMet-Gly-Phe-Pro-) and two corresponding linear hexapeptides with lysine residue on the N- and C-termini of the pentapeptide sequence, Lys-Tyr-DMet-Gly-Phe-Pro and Tyr-DMet-Gly-Phe-Pro-Lys were synthesized by classical and solid phase methods of peptide chemistry. The cyclic analog exhibited significantly prolonged analgesic effect, evaluated by the "tail pinch" method after intracysternal injection to mice. The cycloanalog also had a weak influence on the peripheral opiate receptors of the isolated segment of guinea pig iliac intestine. Addition of the lysine residue to the N-terminus of the pentapeptide sequence enhanced by an order of magnitude the selectivity of binding of the analog with opiate receptors of mu-type.
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7786317
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[Polypeptides from murine peritoneal macrophages recognizing glycosaminylmuramoyl dipeptide].
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By means of radioligand analysis, murine peritoneal macrophages were shown to express several hundreds cell surface high-affinity GMDP-binding sites with a binding constant 350 pM. Photoaffinity labeling followed by SDS-PAGE enabled us to identify inside these cells 32-34 and 38 kDa proteins, specifically binding GMDP. Proteins 32-34 kDa were also detected by Western blotting analysis using biotinylated conjugate of polyacrylamide with immobilized GMDP-Lys [(GMDP-Lys)-PAA-(Bi)] in cell lysate of murine peritoneal macrophages.
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7786315
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[Isolation and properties of carboxypeptidase from the Kamchatka crab Paralithodes camtshatica].
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Homogeneous carboxypeptidase PC from a hematopancreas of kamchatka crab Paralithodes camtshatica was obtained by means of an affinity chromatography on sorbents containing arginine, protamine hydrolysate, and phenylalanine as ligands with an yield 23% and purification degree 37.4. The isolated enzyme has a molecular mass 34 kDa, as evidenced by an SDS-PAGE; pI 3.1; an optimum pH 6.5, as estimated for hydrolysis of Dnp-Ala-Ala-Arg; pH-stability range 5-8 in the presence of Ca2+; a temperature optimum 55 degrees C; and Km 0.4 mM. The carboxypeptidase is activated by Co2+ and Ca2+ ions and is inhibited by EDTA and o-phenanthroline, and therefore, it is a metallocarboxypeptidase. The enzyme can effectively split off C-terminal residues Phe and Tyr, as well as Arg and Lys. Residues Pro, Glu, and Asp cannot be split off, and they stop the cleaving of a preceding bond. Thus, the carboxypeptidase PC of kamchatka crab has a mixed substrate specificity, which is characteristic of carboxypeptidase from crawfish and of microbial carboxypeptidases T and SG. The new carboxypeptidase has an amino acid composition Asp41Thr24Ser22Glu32Pro15Gly32Ala291/2Cys5Val19Met8Ile14Leu20Ty r18Phe8Lys7His4 Arg8Trp4. The N-terminal sequence of the enzyme demonstrate a 40% homology with the N-terminal sequence of carboxypeptidase from crawfish.
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7786316
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[Polyacrolein latex as a solid phase carrier for radioimmunoassay. Comparison with microcrystalline cellulose and polystyrene test tube surface].
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The immunosorbent obtained through a covalent immobilization of antibodies on a polyacrolein latex was studied in comparison with the sorbents based on microcrystalline cellulose and with the surface of polystyrene test tubes in a two-center radioimmunoassay for ferritin. It was shown that the polyacrolein latex provides a covalent binding of up to 75 mg protein per g dry polymer with an immobilization efficiency of 50-70% and a high effective association constant of immobilized antibodies (Ka = 4.5 x 10(9) M-1). The same parameters for the sorbent based on microcrystalline cellulose were 33 mg/g, 25-35%, and 4.3 x 10(8) M-1, respectively. In the radioimmunoassay for ferritin, the immunosorbents based on polyacrolein latex and cellulose ensured a nearly the same analytical sensitivity at the level of (0.7-0.9) x 10(-13) M ferritin and pointed to the possibility of eliminating the "hook-effect". Compared to the immunosorbent based on polystyrene test tubes, the advantages of the polyacrolein latex are the decrease in the minimum detectable concentration (increase in analytical sensitivity), the extension of the dynamical range of analysis, and the absence of the "hook-effect".
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7786314
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[A new differentiation factor from culture media of the HL-60 cell line treated with retinoic acid. Isolation and primary structure determination].
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A new 8.2-kDa protein factor was isolated from cell culture of a promyelocyte leukemic HL-60 cell line that exhibited a differentiation-inducing effect upon the initial cell line. The primary structure of this factor was determined by sequencing the protein (N-terminal region) and the corresponding cDNA. A molecule of the differentiation factor secreted by HL-60 cells consisted of 54 amino acid residues and was glycosylated.
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7786313
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(-)-R-fenoprofen: formation of fenoprofenyl-coenzyme A by rat liver microsomes.
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The thioesterification of fenoprofen (FPF) by rat liver microsomes has been studied using an HPLC method enabling direct quantification of the FPF-CoA produced. Over the concentration range studied (5-400 microM), studies showed the participation of a single CoA ligase in the formation of FPF-CoA, in contrast with the involvement of several isozymes with different affinities, that has been found with ibuprofen (IPF). The Km for the reaction was dependent upon the presence of non-ionic detergent, a concentration of 0.05% Triton X-100 reducing the Km from 397 to 20 microM although the detergent had no effect on Vmax. The microsomal long-chain fatty acid CoA ligase was markedly enantioselective towards (-)-R-FPF and the formation of (-)-R-FP-CoA was inhibited by both the (+)-S enantiomer and palmitic acid.
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7786311
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Effect of eugenol on drug-metabolizing enzymes of carbon tetrachloride-intoxicated rat liver.
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The chemoprotection extended by eugenol against carbon tetrachloride (CCl4) intoxication was established by studies on drug-metabolizing phase I and phase II enzymes. An overall decrease in drug-metabolizing enzymes, namely NADPH-cytochrome c reductase, NADH-cytochrome reductase, coumarin hydroxylase, 7-ethoxy coumarin-O-deethylase, UDP-glucuronyltransferase and glutathione-S-transferase, was observed with CCl4 intoxication, with a subsequent decrease in cytochrome P450 and cytochrome b5 content. CCl4 caused a significant decrease in microsomal phospholipids and the marker enzymes glucose-6-phosphatase and 5'-nucleotidase, and an increase in thiobarbituric acid reactive substances (TBARS). Simultaneous administration of eugenol with CCl4 inhibited the accumulation of TBARS and the decrease in the microsomal phospholipids and marker enzymes. Further, the chemical onslaught imposed by CCl4 on the drug-metabolizing system was removed successfully by eugenol. Eugenol appears to act as an in vivo antioxidant and as a better inducer of phase II enzymes than phase I enzymes. It is therefore suggested that eugenol could be an interesting basic structure for drug design.
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7786312
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Thermodynamic studies with acetylthiocholine on nicotinic receptors of mammalian skeletal muscle in vitro.
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The temperature dependency of binding of acetylthiocholine, a specific nicotinic agonist, to the nicotinic receptor of mammalian skeletal muscle was studied using isotonic contractions of the rat denervated diaphragm preparation in vitro. The dissociation constants at different temperatures (22-39 degrees) were determined by the Furchgott method using alpha-bungarotoxin as an irreversible antagonist. Both free energy of association (delta G zero = -22.93 kJ/mol at 37 degrees) and enthalpy of binding (delta H zero = -58.35 kJ/mol) calculated from Kd (dissociation constant) and slope of lnKd versus 1/T (van't Hoff plot) respectively were found to be negative. The negative entropy value (delta S zero = -0.113 kJ/mol/deg) obtained from the intercept of this van't Hoff plot differs from the large positive value obtained earlier employing radioligand binding studies of the nicotinic receptor of Electrophorus electricus.
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7786310
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Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells.
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Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2.7- and 7.2-fold, respectively, relative to the MCF-7 parental line. No significant changes in glutathione peroxidase and NADPH cytochrome P450 reductase activity, and no increase in microsomal GST and GST pi mRNAs were found in the resistant cells. Treatment with the ALDH substrate octanal sensitized the cells to the cytotoxic effects of 4HC to a modest extent in both MCF-7 and MCF/HC cells [dose modification factor (DMF) of 1.4 and 1.6, respectively]. Depletion of GSH by treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) enhanced the cytotoxic effect of 4HC to a similar extent in both cell lines. By contrast, ethacrynic acid, which inhibited GST activity by > 85% in MCF-7 and MCF/HC cell extracts without depletion of GSH, sensitized the resistant but not the parental cells to 4HC cytotoxicity, indicating the importance of GST as a determinant of 4HC resistance in these cells. This conclusion is supported by the observation that in MCF/HC cells, ethacrynic acid in combination with BSO increased the DMF 3-fold higher than did BSO or EA alone, while in the parental MCF-7 cells ethacrynic acid with BSO had no significant chemosensitization effect over BSO alone. These studies establish that in addition to ALDH, GST overexpression can contribute to acquired resistance of tumor cells to 4HC and, furthermore, suggest that modulators that target the GSH/GST system could be useful in overcoming CPA resistance in the clinic.
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7786309
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Blockade of human neutrophil activation by 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]propoxy]phenoxy]benzoic acid (LY293111), a novel leukotriene B4 receptor antagonist.
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Leukotriene B4 (LTB4), a naturally occurring pro-inflammatory product of arachidonic acid metabolism, has been associated with human inflammatory disease. This study compares the abilities of two LTB4 receptor antagonists, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111) and 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]- 3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), to displace LTB4 binding and their functional blockade of human neutrophil activation. LY293111 inhibited the binding of [3H]LTB4 with a Ki of 25 nM; SC-41930 displayed a similar potency (Ki = 17 nM). In contrast, LY293111 prevented LTB4-induced calcium mobilization with an IC50 = 20 nM, or 40 times more effectively than SC-41930 (IC50 = 808 nM). LY293111 was 300 times more potent than SC-41930 in blocking LTB4-induced CD11b up-regulation on isolated neutrophils. LY293111 also arrested LTB4-induced up-regulation of CD11b on neutrophils in whole human blood. LY293111 was not effective in blocking human neutrophil activation responses induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP), platelet-activating factor (PAF), human recombinant endothelial interleukin-8 (IL-8) or human recombinant complement component 5a (C5a).
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7786308
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Rapid changes in cytochrome P4502E1 (CYP2E1) activity and other P450 isozymes following ethanol withdrawal in rats.
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This study describes the effects of chronic ethanol (ETOH) treatment and withdrawal on the rat hepatic mixed-function mono-oxygenase system. Male Sprague-Dawley rats (150-200 g, 10 per group) were administered ETOH as part of the Lieber-deCarli liquid diet for 3 weeks. Ethanol was removed, and the animals were euthanized at 0, 24, 48, 72 and 168 hr post-withdrawal. Microsomes were prepared, and ethanol-inducible cytochrome P4502E1 (CYP2E1) activity was measured using the enzyme markers N-nitrosodimethylamine demethylase (NDMAd), p-nitrophenol hydroxylase (PNPH) and aniline hydroxylase (AH). Activities were found to be induced significantly after chronic ETOH feeding using all three assays (NDMAd, 5-fold; PNPH, 3.5-fold; AH, 9-fold). Upon ETOH withdrawal, all three activities dropped markedly, with NDMAd and PNPH at control values at 24 hr and all subsequent time points. AH activity remained 3-fold higher than controls at 24, 48 and 72 hr. Western blot analyses showed that immunoreactive CYP2E1 returned to control at 24 hr, consonant with NDMAd and PNPH activities. The prolonged induction of AH activity following ETOH withdrawal indicates that it is not a specific marker of CYP2E1-catalyzed reactions. Collectively, these data are suggestive of a rapid mechanism of CYP2E1 degradation in the rat liver. Of the other parameters investigated in this study, total cytochrome P450 content was increased 2.5-fold after ETOH feeding, with levels dropping markedly 24 hr post-withdrawal. NADPH-dependent cytochrome c reductase activity was unchanged throughout the course of the study. CYP1A1, CYP2B1 and CYP3A activities were assessed by the substrate probes ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD) and erythromycin N-demethylase (ERNd). EROD and PROD were induced significantly by ETOH administration (2-fold) at 0 hr, with EROD remaining elevated over controls 24 hr post-withdrawal. Quantitative western blot analysis of CYP1A1 and CYP2B1 revealed a pattern of immunostaining generally consistent with but less variable than levels predicted by the respective substrate markers. Both proteins were induced significantly by chronic ethanol administration (CYP1A1, 1.9-fold; CYP2B1, 4-fold). Induction of these P450 isoforms persisted for several days following withdrawal. In contrast, immunoreactive CYP1A2 was found to decrease significantly (by 30-40%) during ethanol withdrawal (24, 48, 72, 168 hr). ERNd activity was induced significantly by chronic ETOH feeding (2.5-fold) and remained so for 24 hr into the withdrawal period (2-fold). Immunoreactive CYP3A1 was also induced significantly following ETOH administration (0 hr) and 24 hr following withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)
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7786307
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Characterization of the independent and combined effects of two inhibitors on oxidative drug metabolism in rat liver microsomes.
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To evaluate how two inhibitors influence oxidative drug metabolism, this study investigated the inhibitory effects of mexiletine with cimetidine and mexiletine with lidocaine, both individually and in combination, on the oxidative metabolism of two probe substrates, aminopyrine and aniline in rat liver microsomes. Mexiletine was a competitive inhibitor of aminopyrine N-demethylation, whereas cimetidine was a mixed type of inhibitor (Ki = 2.00 +/- 0.04 and 0.20 +/- 0.02 mM, respectively). For aniline hydroxylation, mexiletine exhibited a mixed type of inhibition, whereas lidocaine was a noncompetitive inhibitor (Ki = 0.60 +/- 0.07 and 8.50 +/- 0.12 mM, respectively). The combined inhibition of either mexiletine with cimetidine or mexiletine with lidocaine on aminopyrine and aniline metabolism was close to the fully additive effects of the individual compounds when their individual concentrations were below a 2-fold Ki concentration, regardless of the apparent kinetic inhibition type. The combined inhibition was less than fully additive when the individual concentrations were twice the Ki or above. These results demonstrate that, when two inhibitors of oxidative drug metabolism are combined, both the Ki values and the concentrations of inhibitors play important roles in determining the extent of additive inhibition of enzyme activity.
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7786306
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Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761.
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Antioxidant mechanisms have been proposed to underlie the beneficial pharmacological effects of EGb 761, an extract from Ginkgo biloba leaves used for treating peripheral vascular diseases and cerebrovascular insufficiency in the elderly. In vitro evidence has been reported that EGb 761 scavenges various reactive oxygen species, i.e. nitric oxide, and the superoxide, hydroxyl, and oxoferryl radicals. However, the ability of EGb 761 to scavenge peroxyl radicals (reactive species mainly involved in the propagation step of lipid peroxidation) has not been investigated. To characterize further the antioxidant action of EGb 761, we measured the protective effects of EGb 761 during: (1) the oxidation of B-phycoerythrin by peroxyl radicals generated in aqueous solution by 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH); and (2) the reaction of luminol or cis-parinaric acid with peroxyl radicals generated from 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN) in liposomes or in human low density lipoprotein (LDL), respectively. To evaluate the peroxyl radical scavenging activity of EGb 761 in a more physiologically relevant model of damage to lipid-containing systems, we also analyzed the effect of the extract on the oxidation of human LDL exposed to the azo-initiators in terms of: (1) accumulation of cholesterol linoleate ester hydroperoxides, (2) depletion of alpha-tocopherol and beta-carotene, and (3) changes in intrinsic tryptophan fluorescence. EGb 761 afforded protection against oxidative damage in all the systems we analyzed; thus, it is an efficient scavenger of peroxyl radicals. This result extends the oxygen radical scavenging properties of the extract and supports the hypothesis of an antioxidant therapeutic action of EGb 761.
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7786304
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Adenylyl cyclase in SH-SY5Y human neuroblastoma cells is regulated by intra- and extracellular calcium.
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Adenylyl cyclase exists as a family of closely related subtypes which differ in their tissue distribution and regulatory properties. Submicromolar rises in [Ca2+]i produced via activation of phospholipase C (PLC) or Ca2+ channel opening, provide a mechanism by which Ca2+/calmodulin (CaM) or protein kinase C (PKC)-sensitive isoforms of adenylyl cyclase can be regulated. In this study we have examined, in detail, the muscarinic (M3) regulation of adenylyl cyclase in SH-SY5Y cells and report a role for both [Ca2+]e and [Ca2+]i. Carbachol (1 mM) and potassium (100 mM) caused a time (T1/2 = 3 and 4 min, respectively) and dose (EC50 = 6.95 microM and 34.7 mM respectively) related increase in cAMP formation. This amounted to an approximate two-fold increase over basal levels. Carbachol and potassium also caused a biphasic increase in [Ca2+]i with basal, peak and plateau values of 118.4 nM, 697.6 nM, 253.0 nM and 104.0 nM, 351.6 nM, 181.5 nM, respectively. Calcium channel blockade with nickel (2.5 mM) abolished potassium-stimulated cAMP formation and rises in [Ca2+]i. However, carbachol-stimulated cAMP formation was significantly decreased only at the later time points, where rises in [Ca2+]i were also essentially abolished. Further evidence for a role for [Ca2+]e and [Ca2+]i is provided by the stimulation of cAMP formation by carbachol in the absence of added Ca2+, followed by a further increase on its re-addition. Carbachol- and potassium-stimulated cAMP formation were inhibited by the CaM antagonist trifluoperazine (100 microM). The mu-opiate agonists, morphine and fentanyl also inhibited carbachol-stimulated cAMP formation. In addition, cAMP formation in SH-SY5Y cell membranes was significantly increased in the presence of Ca2+ (1.46 microM), CaM (200 nM) and forskolin (1 microM). PKC inhibition with Ro 31 8220 did not affect carbachol-stimulated cAMP formation. Taken collectively, these data suggest that SH-SY5Y cells express type 1, and possibly type 8 isoforms of adenylyl cyclase, which can be regulated by intra- and extracellular Ca2+.
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7786305
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Virtual cofactors for an Escherichia coli nitroreductase enzyme: relevance to reductively activated prodrugs in antibody directed enzyme prodrug therapy (ADEPT).
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A nitroreductase enzyme has been isolated from Escherichia coli that has the unusual property of being equally capable of using either NADH or NADPH as a cofactor for the reduction of its substrates which include menadione as well as 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954). This property is shared with the mammalian enzyme, DT diaphorase. The nitroreductase can, like DT diaphorase, also use simple reduced pyridinium compounds as virtual cofactors. The intact NAD(P)H molecule is not required and the simplest quaternary (and therefore reducible) derivative of nicotinamide, 1-methylnicotinamide (reduced), is as effective as NAD(P)H in its ability to act as an electron donor for the nitroreductase. The structure-activity relationship is not identical to that of DT diaphorase and nicotinic acid riboside (reduced) is selective, being active only for the nitroreductase. Irrespective of the virtual cofactor used, the nitroreductase formed the same reduction products of CB 1954 (the 2- and 4-hydroxylamino derivatives in equal proportions). Nicotinic acid riboside (reduced), unlike NADH, was stable to metabolism by serum enzymes and had a plasma half-life of seven minutes in the mouse after an i.v. bolus administration. NADH had an unmeasurably short half-life. Nicotinic acid riboside (reduced) could also be produced in vivo by administration of nicotinic acid 5'-O-benzoyl riboside (reduced). These results demonstrate that the requirement for a cofactor need not be a limitation in the use of reductive enzymes in antibody directed enzyme prodrug therapy (ADEPT). It is proposed that the E. coli nitroreductase would be a suitable enzyme for ADEPT in combination with CB 1954 and a synthetic, enzyme-selective, virtual cofactor such as nicotinic acid riboside (reduced).
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7786303
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Antinociceptive activity of calcitonin and central cholinergic system: behavioural and neurochemical analyses.
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Behavioural and neurochemical analyses were carried out to investigate the relationship between the antinociceptive activity of porcine calcitonin (pCT) and central cholinergic system in mice and rats. Behavioural studies revealed that the antinociceptive activity of pCT encapsulated in sulphatide-containing liposomes injected intravenously into mice was significantly inhibited by atropine sulphate, but not by atropine methylnitrate, and potentiated by physostigmine, but not by neostigmine. Neurochemical studies using rat brain synaptosomes showed that pCT stimulated synaptosomal sodium-dependent high-affinity choline uptake, which was found to be closely associated with acetylcholine (ACh) synthesis (50-60%). This effect was concentration-dependent. In addition, pCT elicited a biphasic effect on ACh release from synaptosomes with an initial brief period of stimulation and subsequent prolonged inhibition. This stimulation was not affected by atropine sulphate, but markedly reduced by incubation in the presence of diltiazem or in a calcium-free medium, indicating that the modulation of ACh release by the peptide may be mediated by calcium fluxes across the synaptosomal membrane independent of cholinergic receptor activation. However, pCT does not affect the activity of synaptosomal acetylcholinesterase. Therefore, the behavioural study in vivo with the neurochemical analysis in vitro suggests that the central cholinergic system may be involved in the antinociceptive activity of calcitonin.
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7786302
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Photosensitized inhibition of growth factor-regulated protein kinases by hypericin.
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The naphthodianthrone hypericin causes a photosensitized inhibition of protein kinases involved in growth factor signalling pathways. Nanomolar concentrations of hypericin inhibit the protein tyrosine kinase activities (PTK) of the epidermal growth factor receptor and the insulin receptor, while being ineffective towards the cytosolic protein tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. Photosensitized inhibition by hypericin is not restricted to receptor-PTKs since the Ser/Thr protein kinases (protein kinase CK-2, protein kinase C and mitogen-activated kinase) are also extremely sensitive to inhibition (IC50 value for protein kinase CK-2 = 6 nM). A comparison of the hypericin-mediated inhibition of the epidermal growth factor-receptor PTK and protein kinase CK-2 revealed that the inhibition is irreversible, strictly dependent upon irradiation of the enzyme-inhibitor complex with fluorescent light and likely mediated by the formation of radical intermediates (type I mechanism). Although the exact molecular basis for the selectivity of enzyme inhibition by hypericin remains unknown, our results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin.
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7786301
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Modification of DNA bases by anthralin and related compounds.
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Modification of bases in calf thymus DNA by treatment with the antipsoriatic drug anthralin was studied. The products of DNA bases were identified and their yields measured by gas chromatography-mass spectrometry with selected ion monitoring. Treatment of calf thymus DNA with anthralin significantly enhanced the amount of modified bases above control levels. Purine bases were modified to products identical with those known to be typical of DNA damage induced by hydroxyl radicals. The yields of Fapy-adenine, 8-hydroxyadenine, Fapy-guanine, and 8-hydroxyguanine were maximally increased at an anthralin concentration of 75 microM. A variety of structural analogues of anthralin were also tested at 75 microM were either weaker or stronger hydroxylating agents. It is likely that damage to DNA bases induced by anthrones contributes to their antiproliferative activity. The pharmacological implications of these characteristics of the action of anthralin on DNA bases are discussed.
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7786300
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Formation of mono- and diglucuronides and other glycosides of benzo(a)pyrene-3,6-quinol by V79 cell-expressed human phenol UDP-glucuronosyltransferases of the UGT1 gene complex.
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Glucuronidation of quinols of polycyclic aromatic hydrocarbons (PAHs) represents an important detoxication pathway preventing toxic quinone/quinol redox cycles. Therefore, mono- and diglucuronide formation of benzo(a)pyrene-3,6-quinol was investigated and compared to that of structurally related 3,6-dihydroxychrysene and simple phenols (1-naphthol and 4-methylumbelliferone) using V79 cell-expressed human UGT1.6 (= P1) and human UGT1.7 (= P4). Properties of human UGT1.6 were compared to those of the rat ortholog. Cofactors related to UDP-glucuronic acid such as UDP-galacturonic acid and UDP-glucose were also studied. It was found that rat and human UGT1.6 and human UGT1.7 catalyse monoglucuronide formation of planar PAH quinols. Diglucuronide formation was only detectable with human UGT1.7. The UGT isozymes studied also formed galacturonides and, although only to a minor extent, glucosides. Rat UGT1.6 (but not the human ortholog) catalysed digalacturonide formation of benzo(a)pyrene-3,6-quinol; the in vivo significance of galacturonide formation remains to be established. The results suggest that planar PAH phenols and quinols are conjugated more efficiently by human UGT1.7 than by UGT1.6, which preferentially conjugates simple planar phenols.
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7786299
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Effects of the phosphatase inhibitor calyculin A on the phosphorylation of C-protein in mammalian ventricular cardiomyocytes.
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The effects of inhibitors of protein phosphatase activity on C-protein phosphorylation were studied in preparations from mammalian ventricles. Calyculin A (CyA), an inhibitor of type 1 and 2A protein phosphatases, was studied. CyA concentration- and time-dependency increased the phosphorylation state of C-protein in isolated 32P-labelled guinea pig ventricular cardiomyocytes. C-protein was identified by its reaction with a polyclonal antibody and immunoprecipitation. It is concluded that C-protein in intact cardiomyocytes could be a substrate for type 1 and 2A protein phosphatases.
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7786298
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1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine--a methoxy ether lipid inhibiting platelet activating factor-induced platelet aggregation and neutrophil oxidative metabolism.
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Whether or not two alkylglycerols could initiate a functional response in human platelets or modify responses induced by platelet activating factor (PAF) was evaluated. It was found that 1-100 microM 1-O-hexadecyl-2-metoxy-glycero-3-phosphatidylcholine (Et-16-OCH3) induced platelet aggregation but 1-O-hexadecyl-sn-glycerol (chimyl alcohol; CA) did not. Et-16-OCH3-induced platelet aggregation was abolished by pretreatment with the PAF receptor antagonist WEB 2086. While CA had no effect on platelet aggregation induced by PAF, pretreatment with Et-16-OCH3 (0.1 microM or higher) significantly inhibited platelet aggregation induced by PAF, but had no effect on aggregation caused by ADP, thrombin or phorbol myristate acetate (PMA). A receptor binding study using radiolabelled [3H]WEB 2086 showed that Et-16-OCH3 exerts its actions through interaction with the PAF receptor. Moreover, Et-16-OCH3 inhibited neutrophil chemiluminescence responses induced by PAF, but not reactions to PMA or a formyl peptide. Finally, 1 microM Et-16-OCH3 induced a rise in the intracellular calcium concentration in platelets equal to that induced by PAF and also had an calcium ionophore-like effect at 100 microM. Thus, this study shows that Et-16-OCH3 is both a potent inducer of platelet aggregation and an inhibitor of PAF-induced platelet aggregation and neutrophil chemiluminescence, through interaction with the PAF receptor.
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7786297
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Sulphoxide reduction by rat intestinal flora and by Escherichia coli in vitro.
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The caecal microflora from female rats show a greater ability to reduce the sulphoxide group of sulindac than either the liver or kidneys. Studies on sulphoxide reduction by Escherichia coli showed that NADH, NADPH and dithiothreitol (DTT), but not acetaldehyde could act as cofactors. The cytosolic fraction was responsible for about 90%, 80% and 60% of the total reducing activity with sulindac, diphenyl sulphoxide and sulphinpyrazone, respectively. The main NADPH linked activity in the E. coli cytosol was dependent on thioredoxin, since the activity was essentially abolished by passing through a G50 column or by the addition of anti-thioredoxin anti-serum. Partial purification and separation of sulphoxide reducing activity by DEAE-cellulose chromatography separated two main protein bands, each of which possessed sulindac reducing activity. The importance of thioredoxin for much of the NADPH dependent activity was confirmed but the eluate fractions also showed the presence of other activities with NADH, NADPH and DTT that were independent of thioredoxin. Incubation of the DEAE-cellulose eluate fractions with flosequinan and sulphinpyrazone showed that the reducing activity in the two main protein peaks showed different substrate specificities and that there were multiple sulphoxide reductase systems present in E. coli cytosol.
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7786296
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Sulphoxide reduction by rat and rabbit tissues in vitro.
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The reduction of sulindac, sulphinpyrazone and diphenyl sulphoxide to their thioether analogues has been studied in vitro using rat and rabbit tissues. Sulindac reduction was about 10-fold higher in homogenates of rat kidney and liver than in other tissues although the tissue differences decreased when dithiothreitol was used as a co-factor. The greatest sulindac reducing activity in rat liver was in the cytosolic fraction whereas reoxidation of the thioether back to the sulphoxide was largely in the microsomal fraction. Studies using NADPH/NADH, acetaldehyde and dithiothreitol as cofactors showed that aldehyde oxidase was the main sulindac reducing system in rat and rabbit liver cytosols but not in renal cytosols where reduction was probably linked to the thioredoxin system, as reported previously. Menadione and hydralazine caused essentially complete inhibition of sulindac reduction by hepatic but not renal cytosol and the inhibition was dependent on preincubation of the enzyme with the inhibitor, which is indicative of aldehyde oxidase activity. Little reduction of sulphinpyrazone or diphenyl sulphoxide was detected with rat or rabbit kidney or renal cytosols, although increased reduction was detected when acetaldehyde was added as a cofactor to rabbit and rat liver cytosols. The data indicate that different enzyme systems are responsible for sulphoxide reduction in the liver and kidney.
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7786295
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Inhibition of tumor necrosis factor by curcumin, a phytochemical.
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Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) induces the production of interleukin-1 beta (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 microM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.
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7786292
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A model for repair of radiation-induced DNA double-strand breaks in the extreme radiophile Deinococcus radiodurans.
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The bacterium Deinococcus (formerly Micrococcus) radiodurans and other members of the eubacterial family Deinococaceae are extremely resistant to ionizing radiation and many other agents that damage DNA. Stationary phase D. radiodurans exposed to 1.0-1.5 Mrad gamma-irradiation sustains > 120 DNA double-strand breaks (dsbs) per chromosome; these dsbs are mended over a period of hours with 100% survival and virtually no mutagenesis. This contrasts with nearly all other organisms in which just a few ionizing radiation induced-dsbs per chromosome are lethal. In this article we present an hypothesis that resistance of D. radiodurans to ionizing radiation and its ability to mend radiation-induced dsbs are due to a special form of redundancy wherein chromosomes exist in pairs, linked to each other by thousands of four-stranded (Holliday) junctions. Thus, a dsb is not a lethal event because the identical undamaged duplex is nearby, providing an accurate repair template. As addressed in this article, much of what is known about D. radiodurans suggests that it is particularly suited for this proposed novel form of DNA repair.
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7786290
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The channels model of nuclear matrix structure.
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The specificity of eukaryotic DNA organization into loops fixed to the nuclear matrix/chromosomal scaffold has been studied for more than fifteen years. The results and conclusions of different authors remain, however, controversial. Recently, we have elaborated a new approach to the study of chromosomal DNA loops. Instead of characterizing loop basements (nuclear matrix DNA), we have concentrated our efforts on the characterization of individual loops after their excision by DNA topoisomerase II-mediated DNA cleavage at matrix attachment sites. In this review the results of applying this mapping approach are compared with the results and conclusions from studies of nuclear matrix DNA. An attempt is also made to reconsider all data about the specificity of DNA interactions with the nuclear matrix and to suggest a model of spatial organization of the eukaryotic genome which resolves apparent contradictions between these data.
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7786291
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Model systems in developmental biology.
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The practical criteria by which developmental biologists choose their model systems have evolutionary correlates. The result is a sample that is not merely small, but biased in particular ways, for example towards species with rapid, highly canalized development. These biases influence both data collection and interpretation, and our views of how development works and which aspects of it are important.
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7786287
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Seminal plasmin.
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The importance of seminal plasma in fertilization was appreciated as early as 1677 and would thus hardly seem a source for the search of antibacterial agents. The observation that seminal plasma had the ability to inhibit the growth of microorganisms in 1940 led to a systematic search for molecules possessing antimicrobial activity in addition to factors that might have a role in reproductive physiology. Extensive investigations led to the discovery in bovine seminal fluid of a 47-residue peptide, possessing potent antimicrobial activity as well as calcium transport modulatory properties in bovine sperm. We describe in this article the two, apparently unrelated, biological activities of this peptide.
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7786289
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A radical approach to enzyme catalysis.
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Free radicals are generally perceived as highly reactive species which are harmful to biological systems. There are, however, a number of enzymes that use carbon-based radicals to catalyse a variety of important and unusual reactions. The most prominent example is ribonucleotide reductase, an enzyme which is crucial for the synthesis of DNA. In general, radicals are used to remove hydrogen from unreactive positions in the substrate, and in this way the substrate is activated to undergo chemical transformations that would otherwise be difficult to achieve. Several different mechanisms have evolved which allow enzymes to generate and maintain radicals in increasingly aerobic environments. An unexpected finding is the existence of stable protein-based radicals, residing on a variety of amino-acid side chains, which serve to link the radical-generating and catalytic sites and to store the radical between turnovers.
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7786288
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Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function.
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Reversible acetylation at the epsilon-amino group of lysines located at the conserved domain of core histones is supposed to play an important role in the regulation of chromatin structure and its transcriptional activity. One promising strategy for analyzing the precise function of histone acetylation is to block the activities of acetylating or deacetylating enzymes by specific inhibitors. Recently, two microbial metabolites, trichostatin A and trapoxin, were found to be potent inhibitors of histone deacetylases. Trichostatin A reversibly inhibits the mammalian histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme. The histone deacetylase from a trichostatin A-resistant cell line is resistant to trichostatin A, indicating that the enzyme is the primary target. Both of the agents induce a variety of biological responses of cells such as induction of differentiation and cell cycle arrest. Trichostatin A and trapoxin are useful in analyzing the role of histone acetylation in chromatin structure and function as well as in determining the genes whose activities are regulated by histone acetylation.
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